83 results on '"MARCOM"'
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2. Abstract PD18-01: Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033)
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Tarantino, Paolo, primary, Tayob, Nabihah, additional, Dang, Chau T, additional, Yardley, Denise, additional, Isakoff, Steven J., additional, Valero, Vicente, additional, Faggen, Meredith, additional, Mulvey, Therese, additional, Bose, Ron, additional, Weckstein, Douglas, additional, Wolff, Antonio C., additional, Reeder-Hayes, Katherine, additional, Rugo, Hope, additional, Ramaswamy, Bhuvaneswari, additional, Zuckerman, Dan, additional, Hart, Lowell, additional, Gadi, Vijayakrishna K., additional, Constantine, Michael, additional, Cheng, Kit, additional, Garrett, Audrey Merrill, additional, Marcom, Paul K., additional, Albain, Kathy S., additional, DeFusco, Patricia, additional, Tung, Nadine, additional, Ardman, Blair, additional, Nanda, Rita, additional, Jankowitz, Rachel C., additional, Rimawi, Mothaffar, additional, Abramson, Vandana, additional, Pohlmann, Paula R., additional, Van Poznak, Catherine, additional, Forero-Torres, Andres, additional, Liu, Minetta C., additional, Ruddy, Kathryn, additional, Zheng, Yue, additional, Barroso-Sousa, Romualdo, additional, Waks, Adrienne, additional, DeMeo, Michelle K., additional, DiLullo, Molly K., additional, Curigliano, Giuseppe, additional, Burstein, Harold, additional, Partridge, Ann, additional, Winer, Eric, additional, Viale, Giuseppe, additional, Hui, Winnie, additional, Mittendorf, Elizabeth A., additional, Schneider, Bryan P., additional, Prat, Aleix, additional, Krop, Ian, additional, and Tolaney, Sara, additional
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- 2023
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3. Abstract P4-02-05: Predictors of long-term durable response in de novo HER2 positive metastatic breast cancer and the real world treatment experience at two institutions
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Smith, Claire E., primary, Marcom, Paul K., additional, Zahi, Mitri, additional, and Ko, Naomi, additional
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- 2023
- Full Text
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4. Abstract PD2-05: Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041)
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Roberto A. Leon-Ferre, Antonino B. D'Assoro, Matthew Bidwell Goetz, Khandan Keyomarsi, Brendan P. McMenomy, Vera J. Suman, Ingrid A. Mayer, Amy S. Clark, Timothy J. Hobday, Claudine Isaacs, James N. Ingle, Tufia C. Haddad, Ciara C. O’Sullivan, Prema P. Peethambaram, Minetta C. Liu, Sun Young Oh, Aki Morikawa, Jodi M. Carter, Meghan Sri Karuturi, Karthik V. Giridhar, Erica L. Mayer, and Paul K. Marcom
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Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Internal medicine ,Alisertib ,medicine ,Endocrine system ,business ,medicine.drug - Abstract
Background: In ER+ breast cancer (BC) models, Aurora A kinase (AURKA) activation is associated with expansion of CD44+/CD24low/- tumor initiating cells, down-regulation of ERα, and endocrine therapy resistance. Alisertib, a selective AURKA inhibitor, can restore ERα expression and endocrine sensitivity. Early phase studies evaluating alisertib alone or with fulvestrant for ER+ metastatic BC (MBC) demonstrated a favorable safety profile and promising antitumor activity [Haddad, Breast Cancer Res Treat. 2018]. A phase II trial was conducted to determine if the addition of fulvestrant to alisertib improved objective response rate (ORR) and to assess clinical activity of alisertib alone or with fulvestrant in patients (pts) with prior fulvestrant and CDK 4/6 inhibitor (CDK 4/6i). Methods: Pts were randomized 1:1 to Arm A, alisertib (50 mg PO BID Days 1-3, 8-10, 15-17 q 28 days) or Arm B, alisertib with fulvestrant (500 mg IM Day 1, 15 for Cycle 1 and q 28 days thereafter). Eligibility included postmenopausal women, history of ER+ BC, prior fulvestrant, ≤ 2 prior chemotherapy lines, and measurable disease. Stratification factors included prior CDK4/6i, ER level ( 6 cycles), overall survival, duration of response (DoR), and safety. Blood and tumor specimens were collected at baseline, end of Cycle 1, and progression. Results: Pts enrolled July 2017 - November 2019 with 118 pre-registered, 96 registered, and 90 evaluable for the primary endpoint (Arm A: 45, Arm B: 45). Median age was 60 (range 33, 85). Nearly all received prior fulvestrant (n=89, 98.9%), aromatase inhibitor (n=83, 92.2%), and CDK4/6i (n=88, 97.8%). Most had secondary endocrine resistance (n=71, 78.9%). Pre-registration biopsy for ER was positive in 84 pts (86.7%) and negative in 6 pts (13.3%). More pts on Arm B had prior everolimus (A: 35.6%, B: 57.8%) and prior chemotherapy (A: 44.4%, B: 55.6%) for MBC. The ORR for alisertib and fulvestrant was 20.0% (90% CI: 10.9-32.3%), not significantly greater than alisertib alone 17.8% (90% CI: 9.2-29.8%). The 24-week CBR for Arm A was 42.2% (90% CI: 29.7-55.6%; n=19, including 7 PR) and Arm B was 31.1% (90% CI: 19.9-44.3%; n=14, including 8 PR). As of July 1, 2020, the median DoR was not reached in either arm. The median PFS time was 5.6 months (95% CI: 3.9 - 9.3) for Arm A and 5.1 months (95%CI: 3.8 - 7.6) for Arm B. Seventeen pts (18.9%) remain on treatment (A: 12, B: 5) having received at least 11 cycles (range up to 32+ cycles). At least one dose reduction was required for pts (A: 19, B: 18), most commonly due to neutropenia. The most common severe (grade ≥3) adverse events included neutropenia (n=19, 42.2% in each arm), anemia (A: 15.6%, B: 8.8%), and fatigue (n=5, 11.1% Arm B only). Pts discontinued therapy due to disease progression equally in each arm (n=28, 62.2%), however more pts on Arm B (n=12) than Arm A (n=5) discontinued therapy due to toxicity, refusal or other reasons. Conclusion: While the addition of fulvestrant to alisertib did not improve ORR, promising clinical activity with alisertib monotherapy was observed overall and notably for pts with endocrine and CDK 4/6i-resistant MBC. More severe toxicities and treatment discontinuation were observed in pts receiving combination therapy. Correlative blood (CTC/cfDNA) and tissue (AURKA, ERα, and stemness biomarkers) studies are underway. Citation Format: Tufia Haddad, Antonino D'Assoro, Vera Suman, Jodi Carter, Brendan McMenomy, Erica Mayer, Meghan Karuturi, Aki Morikawa, Paul Marcom, Claudine Isaacs, Sun Young Oh, Amy Clark, Ingrid Mayer, Khandan Keyomarsi, Roberto Leon-Ferre, Karthik Giridhar, Ciara O'Sullivan, Prema Peethambaram, Timothy Hobday, Minetta Liu, James Ingle, Matthew Goetz. Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-05.
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- 2021
5. Abstract PD18-02: Adjuvant Paclitaxel and Trastuzumab Trial (APT) for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Breast Cancer: final 10-year analysis
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Sara Tolaney, Paolo Tarantino, Noah Graham, Nabihah Tayob, Chau T Dang, Denise Yardley, Beverly Moy, Paul K. Marcom, Kathy S. Albain, Hope Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa Carey, Romualdo Barroso-Sousa, Michelle K. DeMeo, Molly K. DiLullo, Ann Partridge, Adrienne Waks, Clifford Hudis, Ian Krop, Harold Burstein, Aleix Prat, and Eric Winer
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Cancer Research ,Oncology - Abstract
Background: The APT trial evaluated the activity of adjuvant paclitaxel and trastuzumab (TH) among patients with small, node negative HER2+ breast cancer. This regimen showed a 7-year invasive disease-free survival (iDFS) of 93%, a recurrence-free interval (RFI) of 97.5% with only four (1.0%) distant recurrences, and a 7-year overall survival (OS) of 95%. In this end-of-study analysis, we report the survival outcomes at 10 years and assess the role of HER2DX testing in predicting long-term outcomes with adjuvant TH. Methods: APT was a single-arm multicenter investigator-initiated phase II study in which patients with HER2+ breast cancer with tumors ≤3 cm and negative nodes (one single micrometastatic node allowed) received IV weekly paclitaxel (80 mg/m2) with IV weekly trastuzumab for 12 weeks, followed by IV trastuzumab for 9 months. The primary endpoint was 3-year iDFS. Here we report 10-year iDFS, RFI, breast cancer–specific survival (BCSS) and OS. In an exploratory analysis, the risk of recurrence was evaluated with the HER2DX genomic assay. Results: A total of 410 patients were enrolled from October 2007 to September 2010, of which 406 started the study treatment and were included in the intent to treat analysis. Median age at enrollment was 55 years (range, 24 to 85 years), and most patients (67%) had hormone receptor (HR)-positive disease. Fifty percent of patients had tumors 1.0 cm or smaller and only 9% of patients had tumors between 2 cm to 3 cm. Mean tumor size was 1.1 cm. After a median follow-up of 10.2 years (122 months), 36 iDFS events were observed, consistent with a 10-year iDFS of 89.7% (95% CI, 86.3%-93.1%). Ten-year iDFS was 90.2% (95% CI, 86.3%-94.3%) and 88.5% (95% CI, 82.4%-95.1%) for patients with HR-positive and HR-negative tumors at baseline, respectively. 10-year RFI was 96.8% (95% CI, 95.0%-98.7%), 10-year OS was 94.2% (95% CI, 91.6%-96.8%) and 10-year BCSS was 99.1% (95% CI, 98.1%-100.0%). Of the iDFS events observed in the trial, 6 were non-breast cancer related deaths and 9 were contralateral tumors, all but one locally found to be HER2-negative upon biopsy (Table 1). Among patients experiencing an iDFS event, 7 patients (1.7%) had distant recurrences, including 1 with a T2 tumor, 3 with a T1c tumor and 3 with a T1b tumor. At baseline, 6 of them had HR-positive disease, 1 had HR-negative disease, and 6 had high-grade disease. Upon biopsy of metastatic lesions, 5 of the 7 distant recurrences were locally found to be HER2+, 1 was HER2-negative and 1 had unknown HER2 status. HER2DX testing was conducted on available baseline archival tumor tissue and analyses of patients’ survival outcomes based on the HER2DX score will be presented. Conclusion: After 10 years of follow-up, adjuvant TH confirmed excellent long-term outcomes for small, node-negative HER2+ breast cancer, with a 10-year RFI of 96.8% and a 10-year BCSS of 99.1%. Table 1: iDFS events with adjuvant paclitaxel plus trastuzumab after 10.2 years of follow up Citation Format: Sara Tolaney, Paolo Tarantino, Noah Graham, Nabihah Tayob, Chau T Dang, Denise Yardley, Beverly Moy, Paul K. Marcom, Kathy S. Albain, Hope Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa Carey, Romualdo Barroso-Sousa, Michelle K. DeMeo, Molly K. DiLullo, Ann Partridge, Adrienne Waks, Clifford Hudis, Ian Krop, Harold Burstein, Aleix Prat, Eric Winer. Adjuvant Paclitaxel and Trastuzumab Trial (APT) for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Breast Cancer: final 10-year analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-02.
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- 2023
6. Abstract P4-02-05: Predictors of long-term durable response in de novo HER2 positive metastatic breast cancer and the real world treatment experience at two institutions
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Claire E. Smith, Paul K. Marcom, Mitri Zahi, and Naomi Ko
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Cancer Research ,Oncology - Abstract
Purpose Modern HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR), which can be defined as no progression of disease since initial diagnosis. Clinical and pathologic factors that predict DR continue to be elucidated. Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Methods This is a retrospective study of all patients with de novo HER2+ MBC at two major academic institutions who received at least one dose of trastuzumab between 2012-2019. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor and initial treatment were analyzed as predictors of DR using an unpaired T test, with p< 0.05 chosen as threshold for significance. For patients with DR, time to complete (CR) and partial response (PR) according to RECIST 1.1 were recorded, as was the duration and treatment patterns surrounding trastuzumab and pertuzumab. Patients were defined as having cardiotoxicity if they experienced a decline in cardiac ejection fraction at any point while on trastuzumab therapy leading to treatment delays or discontinuation. Results 96 patients with de novo HER2+ MBC, 28 with DR and 68 with progression, were identified. The average follow up of patients with DR was 90 months (range 27-224), compared to 58 months (range 1-208) in controls. The entire cohort of 96 patients had a median PFS of 23.5 months and a median OS of 88 months. Among the 28 patients with DR, 2 achieved stable disease, 10 patients had documented PR at 4 months on average (range 2-6 months), and 26 patients had CR at 7.7 months on average (range 2-19 months). Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p=0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p< 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p=0.002.) Age, and ER/PR status did not predict DR. (Table 1) Six patients (6.3%) developed reduced ejection fraction requiring treatment interruption or cessation, five in the group who progressed, one in the DR group. Conclusion Nearly a third of patients with de novo HER2+ MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. This suggests that in selected patients, a more aggressive up front approach including surgical resection, and agents such as carboplatin, and trastuzumab deruxtecan deserves further study. Among patients with DR, indefinite trastuzumab administration is the norm with minimal cardiotoxicity but the impact of this on quality of life and financial toxicity are not well described. Table 1: Clinical characteristics of de novo HER2 positive metastatic breast cancer that predict durable response Citation Format: Claire E. Smith, Paul K. Marcom, Mitri Zahi, Naomi Ko. Predictors of long-term durable response in de novo HER2 positive metastatic breast cancer and the real world treatment experience at two institutions [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-05.
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- 2023
7. Abstract PD18-01: Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033)
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Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, and Sara Tolaney
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Cancer Research ,Oncology - Abstract
Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-01.
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- 2023
8. Abstract P2-13-02: Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial)
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P. Kelly Marcom, Ann H. Partridge, Hope S. Rugo, Ron Bose, Denise A. Yardley, Douglas Weckstein, Katherine E. Reeder-Hayes, Harold J. Burstein, Michael Constantine, Rita Nanda, Jiani Hu, Patricia DeFusco, Nadine Tung, William T. Barry, Ian E. Krop, Chau T. Dang, Bhuvaneswari Ramaswamy, Frederick Briccetti, Vijayakrishna K. Gadi, V. Valero, Lorenzo Trippa, Sara M. Tolaney, Kit L. Cheng, Eric P. Winer, Antonio C. Wolff, Lowell L. Hart, Michelle Demeo, Blair Ardman, Steven J. Isakoff, Bryan P. Schneider, Kathryn J. Ruddy, Therese M. Mulvey, Rachel C. Jankowitz, Meredith Faggen, Dan Sayam Zuckerman, Kathy S. Albain, and A. Merrill Garrett
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,Breast cancer 3 ,medicine ,Gynecology ,Chemotherapy ,business.industry ,Oophorectomy ,medicine.disease ,Regimen ,030104 developmental biology ,Oncology ,chemistry ,Trastuzumab emtansine ,030220 oncology & carcinogenesis ,Amenorrhea ,medicine.symptom ,business ,medicine.drug - Abstract
Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.
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- 2020
9. Abstract GS3-08: Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network
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Katherine A. Hoadley, Ian E. Krop, P. Kelly Marcom, Jay Bowen, Joel S. Parker, Anna Maria Storniolo, Nancy E. Davidson, Amy Garrett, Susan G. Hilsenbeck, Rita Nanda, Claudine Isaacs, Toshinori Hinoue, Kristen M. Leraas, Chad J. Creighton, Julie M. Gastier-Foster, Antonio C. Wolff, Lisa A. Carey, Uma R. Chandran, Andrea L. Richardson, Fergus J. Couch, Carey K. Anders, Tari A. King, Benjamin J. Kelly, Minetta C. Liu, Sara E. Coppens, Salma Rezk, Elaine R. Mardis, Larry Norton, Charles M. Perou, W. Fraser Symmans, Marni B McClure, Justin M. Balko, Robyn Burns, Ben Ho Park, Adrian V. Lee, Nan Lin, Mothaffar F. Rimawi, and Peter W. Laird
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,JAM3 ,Cancer ,medicine.disease ,Primary tumor ,Metastatic breast cancer ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,DNA methylation ,medicine ,business ,Exome sequencing - Abstract
Background: It has become increasingly clear that effective treatment of metastatic breast cancer (MBC) requires an in-depth understanding of the molecular differences between primary tumors and metastases. The AURORA US Network was established to collect primary breast cancer-metastasis pairs for multi-platform genomic profiling in order to identify the molecular drivers of metastatic disease. AURORA US has both a retrospective and prospective phase. This is the first report of the retrospective phase. Methods: Archived tissue samples from the primary tumor and at least one distant metastasis were retrospectively collected from 83 MBC patients. Following internal quality assessment, samples from 55 pts, including 105 distinct metastatic lesions, were subject to DNA low pass whole genome and exome sequencing, DNA methylation arrays, and RNA sequencing. Early analyses of these multi-platform data include: DNA methylation, tumor gene expression and microenvironmental signatures, somatic and germline variants, DNA copy number changes, and structural variants between breast primaries and matched metastases. Results: Median age at diagnosis was 49 years (25-76); 32 (58%) were Stage I or II at presentation, 27 (49%) had a family history of breast cancer, and 20 (36%) had a second breast primary. Median disease-free interval before developing MBC was 2 years (range 0-36, 5 patients presented with Stage IV). Median overall survival from initial presentation was 4 years (range 0-37). Median survival after developing MBC was 1 year (range 0-13), with a median of three treatments. Primary tissue samples were banked from 1977-2017 and metastases were banked from 1999-2017. Clinical phenotypes of the primaries included 27 HR+ (49%), 15 triple negative (TNBC, 27%), and 11 HER2+ (20%, 12 missing HER2 status). Intrinsic subtype distribution of the primaries included 17 Basal-like (31%), 17 Luminal A (31%), 7 Normal-like (13%), 5 HER2-enriched (9%), and 1 Luminal B, with 8 pending. All metastases from the Basal-like cases remained Basal-like, while metastases from luminal primaries tended to gain HER2-Enriched subtype features (5/18, p = 0.01). Overall, we identified significant metastasis-enriched alterations in metabolism pathways, an increase in proliferation, and the loss of differentiation signatures and immune infiltrates with progression; the latter being the most pronounced in brain metastases. The most frequent somatic mutations in this cohort were in TP53, NCOR1, and RUNX1. Interestingly, ERBB2, EGFR, and ATM were also mutated in ≥10% of the tumors sequenced. In almost all cases, CpG island hypermethylation was clonally present in the primary tumor and persisted stably in the majority of metastatic lesions. Promoter CpG island hypermethylation was also identified in some metastatic lesions at JAM3, an important cellular adhesion molecule,and this was accompanied by reduced mRNA expression. CONCLUSIONS: Collection of banked primary and metastatic tissue pairs identified a young MBC cohort with a high frequency of breast cancer family history and second breast primaries. Molecular characterization of luminal tumor pairs highlighted acquisition of aggressive traits including increased proliferation and loss of differentiation in the metastases. In contrast, basal-like pairs remained relatively unchanged, except for the loss of immune activation. Ongoing analyses to be presented include clonal heterogeneity and phylogeny, novel metastasis signature discovery, gene fusion, and endogenous retrovirus detection. Citation Format: Tari A King, Minetta C Liu, Marni B McClure, Toshinori Hinoue, Benjamin J Kelly, Chad J Creighton, Jay Bowen, Kristen Leraas, Robyn T Burns, Sara Coppens, Salma Rezk, Amy L Garrett, Justin M Balko, Joel S Parker, Ben H Park, Ian Krop, Carey Anders, Katherine A Hoadley, Julie Gastier-Foster, Mothaffar F Rimawi, Rita Nanda, Nancy U Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J Couch, Elaine R Mardis, Adrian V Lee, Uma Chandran, Peter W Laird, Susan G Hilsenbeck, Larry Norton, Andrea L Richardson, W. Fraser Symmans, Lisa A Carey, Antonio C Wolff, Nancy E Davidson, Charles M Perou, the AURORA US Network. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-08.
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- 2020
10. Abstract P3-08-10: Characterization of oncotype DX recurrence score and chemotherapy utilization patterns in young women (≤40) with early stage ER+/HER-, lymph node negative breast cancer
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Kelly Westbrook, Carey K. Anders, Sarah Sammons, Rachel A. Greenup, ES Hwang, Samantha M. Thomas, Laura H. Rosenberger, Oluwadamilola M. Fayanju, Jennifer K. Plichta, Jeremy Force, Terry Hyslop, Susan Dent, Yi Ren, Paul K. Marcom, and Gretchen Kimmick
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,medicine.diagnostic_test ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Cancer ,Logistic regression ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,Adjuvant therapy ,Stage (cooking) ,Oncotype DX ,business - Abstract
Background: Meta-analyses have demonstrated that young women ≤40 (YW) derive the most benefit from chemotherapy (EBCTCG, Lancet. 1998). Oncotype DX was designed to determine the benefit of chemotherapy in women with ER+/HER2-, node-negative (LN-) breast cancer based on recurrence score (RS). TAILORx reported clinically meaningful benefits in freedom-from-distant recurrence in women Methods: Using the National Cancer Data Base (NCDB), we identified individuals age 25) RS. Age categories were classified as ≤40, 41-50, and >50. Chi-square tests or Fisher’s exact tests were used to compare categorical variables. Logistic regression was used to estimate the association of RS score and age group with adjuvant chemotherapy use, after adjustment for known covariates. Kaplan-Meier curves were used to visualize unadjusted overall survival (OS), and Cox proportional hazards models were used to estimate adjusted OS. Results: 120,051 women were identified, of whom 4,781 were ≤40 years, 24,846 were 41-50, and 90,424 were >50. By age group, 20% of YW had a high RS compared to 12% of women age 41-50 and 15% of women >50 (p50 to receive chemotherapy (p Conclusions: High RS is more common in YW (≤40) than those age 41-50 or >50, and is associated with worse OS. YW with an int or low RS are more likely to receive chemotherapy despite unclear benefit. Chemotherapy was omitted in over half of YW with RS of 16-25, highlighting the uncertainty in clinical practice which will remain until further studies inform optimal systemic treatment specific to YW. 1. Sparano, J.A., et al., Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. New England Journal of Medicine, 2019. 380(25): p. 2395-2405. Citation Format: Sarah Sammons, Yi Ren, Jeremy Force, Oluwadamilola M. Fayanju, Laura H. Rosenberger, Jennifer K. Plichta, Gretchen Kimmick, Kelly Westbrook, Susan Dent, Carey Anders, Samantha M. Thomas, Terry Hyslop, E. S. Hwang, P. K. Marcom, Rachel A. Greenup. Characterization of oncotype DX recurrence score and chemotherapy utilization patterns in young women (≤40) with early stage ER+/HER-, lymph node negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-10.
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- 2020
11. Abstract P3-06-09: Incidence of ROS1 genomic alterations in breast cancer
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Ethan S. Sokol, Mary Love Taylor, Paul K. Marcom, Dale Huang, Jeffrey R. Marks, Monika A. Davare, and Jeremy Force
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Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,Incidence (epidemiology) ,medicine ,ROS1 ,medicine.disease ,business - Abstract
Background: ROS1 is an important proto-oncogene involved in the development of various cancers and increased expression is a poor prognostic feature in breast cancer. Activation of the ROS1 tyrosine kinase receptor has been reported and is being targeted with several FDA approved small molecule inhibitors, primarily in lung cancer. However, the frequency and type of ROS1 alterations in breast cancer have not been fully explored. The purpose of this study was to identify the incidence and type of ROS1 genomic alterations occurring in breast cancer as a prelude to potentially targeting this protein in the setting of metastatic breast cancers that harbor these changes. Methods: We queried 21,125 breast cancer samples (~50% from distant metastatic sites) from the Foundation Medicine breast cancer database, 5,964 breast cancer samples from five publicly available breast cancer databases (MBC Project, INSERM, METABRIC, TCGA, MSK-IMPACT), and 217 breast cancer samples from Project GENIE v6.5 to identify the incidence of ROS1 alterations in breast cancer. We identified fusion partner genes and classified each alteration type into the following categories: fusion, rearrangement, short variant (missense or indel), or copy number variation. A computational approach was used to distinguish somatic from germline single nucleotide polymorphisms in the Foundation Medicine database (Sun et. al., 2018). PolyPhen2 and in vitro analyses were used to investigate the effect of ROS1 nonsynonymous mutations on the ROS1 protein. Using Foundation Medicine, we made associations with ROS1 alterations and receptor status, histologic subtype, metastatic site, tumor mutational burden, and co-occurring mutated genes. Estrogen receptor (ER) status was available for 2,371 samples. HER2 status and all other analyses were identified from the entire cohort. Results: The incidence of any ROS1 alteration across the Foundation Medicine breast cancer database, including variants of unknown significance, was 4.6% and ranged from 1.67% to 6.9% from the five publicly available breast cancer databases and Project GENIE. Foundation Medicine samples revealed 5 (0.024%) breast cancers with ROS1 fusions, 86 (0.41%) with rearrangements, 733 (3.47%) with short nucleotide variants, and 182 (0.86%) with copy number variations. ROS1 alterations occurred similarly in HER2, TNBC, and ER+ breast cancers, 5.24%, 4.5%, and 4.37%, respectively (ns, all p>0.2). Invasive ductal carcinoma, invasive lobular carcinoma, and metaplastic carcinoma harbored ROS1 alterations at 4.35%, 3.65%, and 4.36%, respectively (ns, all p>0.3). ROS1 alterations were significantly associated with metastatic breast cancer spread to the brain (p=0.0005) and lymph nodes (p=0.017). There were 18 gene mutations significantly co-occurring with ROS1 alterations when controlling for multiple comparisons. The top 5 were TP53 (OR 1.55, p=3.12 × 10−8), RB1 (OR 1.66, p=0.0001), NOTCH3 (2.27, p=0.0001), TAF1 (OR 4.82, p=0.0002), and ARID1A (OR 1.71, p=0.0003). Conclusions: A modest incidence of genomic alterations in ROS1 occurs across all breast cancer subtypes and histologies and may be more actionable than currently recognized. New somatic alterations in the ROS1 gene were identified from Foundation Medicine that were not detected in publicly available databases or Project GENIE. Investigations using PolyPhen2 and in vitro analyses of ROS1 gene activation from these newly discovered somatic alterations and other short variant mutations are currently being investigated in our lab with results to be reported. Co-occurring mutations reveal a unique genotype associated with ROS1 alterations that may play a biologic role in ROS1-mediated pathogenesis and should be explored further. ROS1 alterations occurring in breast cancers might be leveraged in an innovative personalized medicine treatment approach for breast cancer patients. Citation Format: Jeremy Force, Ethan S Sokol, Mary Love Taylor, Dale Huang, Paul K Marcom, Monika Davare, Jeffrey Marks. Incidence of ROS1 genomic alterations in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-09.
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- 2020
12. Abstract P1-06-04: Small-molecule screening nominates diverse combination therapies that sensitize BRCA mutant and wild-type triple negative breast cancer to PARP inhibition
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Jeremy Force, Kelly Marcom, Carey K. Anders, Kelly E. Westbrook, Grace R. Anderson, K. L. Blackwell, Sarah Sammons, C Yip, and Kris C. Wood
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Cancer Research ,Oncology ,Poly ADP ribose polymerase ,Mutant ,Wild type ,Cancer research ,Biology ,Small molecule ,Triple-negative breast cancer - Abstract
Background: Triple negative breast cancer (TNBC) remains a heterogeneous clinical phenotype with few, known therapeutic targets. PARP inhibitors (PARPi) are the first approved, targeted therapy in TNBC, limited to germline BRCA mutant (BRCAm) cancers that lack homologous recombination repair capacity. Even in this context, resistance quickly emerges via secondary mutations that restore DNA repair ability. While DNA damage repair is an intriguing target in BRCA wild type (BRCAwt) TNBC due to inherent, genomic instability, PARPi alone have been ineffective in unselected populations. Systematic approaches to define novel drugs that sensitize BRCAwt and BRCAm TNBC to PARPi would greatly improve therapeutic efficacy and durability. Methods: BRCAwt (HCC1806) and BRCAm (SUM149PT) cell lines were screened in duplicate using a 2,100-compound small molecule library. Cell lines were plated in media containing DMSO or sub-lethal doses of the PARPi, olaparib, onto Selleck Bioactive drug plates. Cell viability was assessed after 72 hours, then normalized to vehicle control. Hit cut-offs were predefined as log2 drug/DMSO of ≤ -0.7 with a viability difference greater than 20% -where stringent scoring thresholds were chosen to exceed the full range of scores observed in 816 empty control wells. Hits were sorted by target and pathway to provide mechanistic insight into the synergy of combinations. Drug combinations with the highest potential for near term translation were validated using GI50 viability assays in 9 BRCAwt and BRCAm TNBC cell lines. The most promising combination was further validated via immunoblotting, colony formation, and apoptosis assays. Results: Several drug classes affecting well-known oncogenic signaling pathways conferred sensitivity to PARPi, with more hits in the BRCAm cell line. Relevant druggable targets sensitizing cells to olaparib in BRCAm TNBC that met the predefined cut-point were inhibitors of PI3K (pan-PI3K, PI3Kα and PI3Kβ specific), VEGFR, MEK, EGFR, NF-kB, aurora kinase and several DNA damaging agents. Aurora kinase, EGFR, and NF-kB inhibition sensitized cells to olaparib, yet upon further validation, synergy was mild. The screen identified ATM inhibitors, KU-55933 and KU-60019, as sensitizers of BRCAm cells to olaparib. The potent ATM inhibitor, AZD0156, and olaparib were a highly synergistic combination validated in all 9 BRCAm and BRCAwt TNBC cell lines via cell viability, annexin V, and colony formation assays. Immunoblotting of relevant DNA damage repair proteins showed that olaparib caused upregulation of p-ATM in BRCAm and BRCAwt cells. p-ATM expression decreased in response to combination ATM and PARP inhibition. Attenuated levels of p-ATM resulted in increased levels of p- and T-γH2AX, indicating an accumulation of double stranded DNA breaks. Conclusion: In vitro, inhibition of several relevant, oncogenic pathways yielded sensitivity to PARPi in TNBC. We identified the ATM inhibitor, AZD0156, and olaparib as a potent combination regardless of BRCA status, a finding currently being evaluated in patient-derived in vivo models. Combination ATM plus PARP inhibitor therapy is a promising and feasible approach for near term translation in metastatic TNBC. Citation Format: Sammons S, Yip C, Anderson G, Force J, Marcom K, Westbrook K, Anders CK, Blackwell K, Wood K. Small-molecule screening nominates diverse combination therapies that sensitize BRCA mutant and wild-type triple negative breast cancer to PARP inhibition [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-04.
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- 2019
13. Abstract P3-08-07: Distinct biological signatures describe differences in BRCA mutated subgroups
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Noah D. Kauff, Ilona Stashko, Kent J. Weinhold, Terry Hyslop, S Hwang, Paul K. Marcom, Heather Ann Brauer, Gretchen Kimmick, Afshin Mashadi-Hossein, Edgardo R. Parrilla Castellar, Smita K. Nair, S Davis, Jennifer K. Plichta, Sarah Sammons, Jeremy Force, and Kelly E. Westbrook
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Cancer Research ,education.field_of_study ,animal structures ,endocrine system diseases ,business.industry ,Population ,Wild type ,Cancer ,medicine.disease ,female genital diseases and pregnancy complications ,Germline ,Breast cancer ,Oncology ,Hormone receptor ,Cancer research ,medicine ,Stage (cooking) ,skin and connective tissue diseases ,business ,education ,Hormone - Abstract
Background: BRCA mutated (BRCA+) breast cancers are expected to have increased activation of Homologous Recombination Deficiency (HRD) and altered DNA damage repair pathways when compared to BRCA wildtype (BRCA-). To better understand differences in these populations, biological patterns and immune responses to BRCA+ breast cancers were evaluated. The primary aim of our study was to use novel gene expression tools to assess early stage breast cancers with and without germline BRCA mutations, and within distinct BRCA+ subgroups. Methods: We identified 124 early stage untreated breast cancers with and without BRCA mutations (n = 62 and 62, respectively). Our BRCA- group was matched by hormone receptor (HR) status, age, and stage to the BRCA+ group. The NanoString Breast Cancer 360 panel was applied to RNA isolated from 80 breast tumors (BRCA+ = 39; BRCA- = 41). The BRCA+ group had a BRCA1+ subgroup (n=17) and a BRCA2+ subgroup (n=22). Results: There was a significant increase in two BC360 signatures in both the BRCA1+ and BRCA2+ tumors compared with the BRCA- population: Prosigna™Risk of Recurrence (ROR) score [BRCA1+: HR: 1.142 (95% CI 1.019, 1.279), p=0.02; BRCA2+: HR: 1.321 (95% CI 1.190, 1.466), p Conclusions: In early stage BRCA+ breast cancer, tumors have higher ROR and increased HRD signature scores compared to BRCA- tumors. Furthermore, BRCA1+ and BRCA2+ tumors have both signature and single gene expression differences when compared to BRCA- tumors, indicating distinct subgroup-related biology. The greater correlation of BRCA1+ tumors with basal-like biology and BRCA2+ tumors with aggressive hormonal biology confirms these trends. Distinctions in hormone receptor signaling, DNA-damage pathways, and microenvironment/inflammatory features between BRCA1 and BRCA2 associated cancers suggest a need for different prevention and therapeutic strategies for each of these breast cancer subtypes. The unique biological patterns identified here should be further evaluated as predictive or prognostic tools that could be translated into clinical care for early stage BRCA+ patients. Citation Format: Force J, Plichta J, Stashko I, Kimmick G, Westbrook K, Sammons S, Hwang S, Hyslop T, Kauff N, Castellar E, Nair S, Weinhold K, Davis S, Mashadi-Hossein A, Brauer HA, Marcom PK. Distinct biological signatures describe differences in BRCA mutated subgroups [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-07.
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- 2019
14. Abstract CT026: A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER
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Ma, Cynthia X., primary, Luo, Jingqin, additional, Freedman, Rachel A., additional, Pluard, Timothy, additional, Nangia, Julie, additional, Lu, Janice, additional, Valdez-Albini, Frances, additional, Cobleigh, Melody, additional, Jones, Jason, additional, Lin, Nancy U., additional, Winer, Eric, additional, Marcom, P. Kelly, additional, Thomas, Shana, additional, Anderson, Jill, additional, Haas, Brittney, additional, Hamann, Kimberly M., additional, Bryce, Richard, additional, Lalani, Alshad S., additional, Carey, Lisa, additional, Goetz, Matthew, additional, Gao, Feng, additional, Kimmick, Gretchen, additional, Pegram, Mark, additional, Ellis, Matthew J., additional, and Bose, Ron, additional
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- 2021
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15. Abstract CT144: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
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Marcom, P. Kelly, primary, Price, Trevor T., additional, Murray, Andrew S., additional, Fogler, William E., additional, Magnani, John L., additional, Thackray, Helen, additional, Feldman, Eric, additional, and Sipkins, Dorothy, additional
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- 2021
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16. Abstract PS16-06: Identification of pathogenic FGFR1, FGFR2, and FGFR3 alterations in cell-free DNA (cfDNA) from patients with metastatic breast cancer
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Taylor, Mary Love, primary, Mayro, Benjamin, additional, Drusbosky, Leylah, additional, Batchelder, Robin, additional, Marcom, P. Kelly, additional, Anders, Carey, additional, and Force, Jeremy, additional
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- 2021
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17. Abstract SS1-11: Comprehensive analysis of health services, sociodemographic, clinical, and genomic factors driving locally advanced breast cancer mortality via a first-in-kind linkage of SEER-Medicare data with physical tumor samples
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Robinson, Timothy J, primary, Wilson, Lauren, additional, Marcom, Paul K, additional, Troester, Melissa, additional, Lynch, Charles F, additional, Hernandez, Brenda, additional, Castellar, Edgardo P, additional, Brauer, Heather Ann, additional, Enewold, Lindsey, additional, and Dinan, Michaela, additional
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- 2021
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18. Abstract GS1-05: TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT)
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Tolaney, Sara M, primary, Trippa, Lorenzo, additional, Barry, William, additional, Hu, Jiani, additional, Dang, Chau, additional, Yardley, Denise, additional, Isakoff, Steven, additional, Valero, Vicente, additional, Faggen, Meredith, additional, Mulvey, Therese, additional, Bose, Ron, additional, Weckstein, Douglas, additional, Wolff, Antonio, additional, Reeder-Hayes, Katherine, additional, Rugo, Hope, additional, Ramaswamy, Bhuvaneswari, additional, Zuckerman, Dan, additional, Hart, Lowell, additional, Gadi, Vijayakrishna K., additional, Constantine, Michael, additional, Cheng, Kit, additional, Briccetti, Frederick, additional, Schneider, Bryan, additional, Garrett, Merrill, additional, Marcom, Kelly, additional, Albain, Kathy, additional, DeFusco, Patricia, additional, Tung, Nadine, additional, Ardman, Blair, additional, Nanda, Rita, additional, Jankowitz, Rachel, additional, Demeo, Michelle, additional, Partridge, Ann, additional, Burstein, Harold, additional, Winer, Eric P., additional, and Krop, Ian, additional
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- 2020
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19. Abstract GS6-03: Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031)
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Tung, Nadine, primary, Arun, Banu, additional, Hofstatter, Erin, additional, Hacker, Michele R., additional, Toppmeyer, Deborah L., additional, Isakoff, Steven J., additional, Borges, Virginia, additional, Legare, Robert D., additional, Isaacs, Claudine, additional, Wolff, Antonio C., additional, Marcom, Paul K., additional, Mayer, Erica L., additional, Lange, Paulina B., additional, Goss, Andrew J., additional, Krop, Ian E., additional, Winer, Eric P., additional, Schnitt, Stuart J., additional, and Garber, Judy E., additional
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- 2020
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20. Abstract PD10-02: Patient reported outcomes from the adjuvant trastuzumab emtansine (T-DM1) vs. paclitaxel + trastuzumab (TH) (ATEMPT) trial (TBCRC 033)
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Partridge, Ann, primary, Zheng, Yue, additional, Rosenberg, Shoshana, additional, Gelber, Richard, additional, Gelber, Shari, additional, Barry, William, additional, Dang, Chau, additional, Yardley, Denise, additional, Isakoff, Steven, additional, Valero, Vicente, additional, Faggen, Meredith, additional, Mulvey, Therese, additional, Bose, Ron, additional, Weckstein, Douglas, additional, Wolff, Antonio, additional, Reeder-Hayes, Katherine, additional, Rugo, Hope, additional, Ramaswamy, Bhuvaneswari, additional, Zuckerman, Dan, additional, Hart, Lowell, additional, Gadi, Vijayakrishna, additional, Constantine, Michael, additional, Cheng, Kit, additional, Briccetti, Frederick, additional, Schneider, Bryan, additional, Garrett, Merrill, additional, Marcom, P. Kelly, additional, Albain, Kathy, additional, Defusco, Patricia, additional, Tung, Nadine, additional, Ardman, Blair, additional, Nanda, Rita, additional, Jankowitz, Rachel, additional, DeMeo, Michelle, additional, Burstein, Harold, additional, Winer, Eric P., additional, Krop, Ian, additional, and Tolaney, Sara, additional
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- 2020
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21. Abstract P2-13-02: Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial)
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Ruddy, Kathryn J., primary, Trippa, Lorenzo, additional, Hu, Jiani, additional, Barry, William T., additional, Dang, Chau T., additional, Yardley, Denise A., additional, Isakoff, Steven J., additional, Valero, Vincente V., additional, Faggen, Meredith G., additional, Mulvey, Therese M., additional, Bose, Ron, additional, Weckstein, Douglas J., additional, Wolff, Antonio C., additional, Reeder-Hayes, Katherine E., additional, Rugo, Hope S., additional, Ramaswamy, Bhuvaneswari, additional, Zuckerman, Dan S., additional, Hart, Lowell L., additional, Gadi, Vijayakrishna K., additional, Constantine, Michael, additional, Cheng, Kit L., additional, Briccetti, Frederick M., additional, Schneider, Bryan P., additional, Garrett, A. Merrill, additional, Marcom, P. Kelly, additional, Albain, Kathy S., additional, DeFusco, Patricia A., additional, Tung, Nadine M., additional, Ardman, Blair M., additional, Nanda, Rita, additional, Jankowitz, Rachel C., additional, DeMeo, Michelle K., additional, Burstein, Harold J., additional, Winer, Eric P., additional, Krop, Ian E., additional, Partridge, Ann H., additional, and Tolaney, Sara M., additional
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- 2020
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22. Abstract CT144: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
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Trevor T. Price, Andrew S. Murray, William E. Fogler, John L. Magnani, P. Kelly Marcom, Eric J. Feldman, Dorothy A. Sipkins, and Helen M. Thackray
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Cancer Research ,Tumor microenvironment ,business.industry ,Cancer ,medicine.disease ,Primary tumor ,Metastatic breast cancer ,Immunophenotyping ,medicine.anatomical_structure ,Immune system ,Oncology ,Cancer research ,Myeloid-derived Suppressor Cell ,Medicine ,Bone marrow ,business - Abstract
Pre-clinical and clinical data suggest that the bone marrow (BM) environment provides breast cancer (BC) cells a protective haven against chemotherapeutic insult, endocrine therapies, and immune recognition. Novel agents that intercept cross-talk between BC cells and the host could therefore improve the depth of response to therapies and potentially increase overall survival in metastatic BC. We have previously shown that bone metastatic BC cells reside in perivascular niches expressing high levels of SDF-1α (CXCL12) and E-selectin, two molecules for which emerging data have demonstrated a significant role in metastatic BC progression. Our prior pre-clinical studies have shown that E-selectin inhibition specifically prevents circulating BC cells from homing to the BM, whereas CXCR4 blockade mobilizes micrometastases from the marrow into circulation, where they may be sensitized to chemotherapeutic cell kill. Given the normal role of these molecules in host immune responses, E-selectin/CXCR4 blockade has additional potential to impact the tumor immune microenvironment. GMI-1359 is a small molecule, glycomimetic compound with dual inhibitory activity against E-selectin and CXCR4. We hypothesize that GMI-1359 can block E-selectin and CXCR4 binding to E-selectin ligands and SDF-1, disrupting the protective effects of the bone microenvironment on tumor cells. A single-center, phase 1b, open-label, single and multiple ascending dose study (NCT04197999) is therefore evaluating GMI-1359 in patients with HR+ metastatic breast cancer with bony metastases who are stable or minimally progressive on endocrine therapy, with or without a CDK4/6 inhibitor. To date, 2 patients have been enrolled and received single monthly doses of 3.5, 5.0 and 7.0 mg/kg followed by 3 daily doses of 7 mg/kg. Both patients have completed treatment with no dose limiting toxicities observed. Coincident with GMI-1359 administration at all dose levels, we observed mobilization of CD34+ cells coupled with a reduction in elevated serum sE-selectin levels, demonstrating the dual functionality of the compound. Initial peripheral blood immunophenotype data on one patient revealed a redistribution of myeloid derived suppressor cells and a shift in macrophage polarization from M2 to M1. Notably, we observed similar immune alterations in ongoing preclinical studies in the E0771 syngeneic BC mouse model. We found that orthotopically-engrafted mice treated with single agent 1359 had a significant increase in the ratio of CD8/Tregulatory cells isolated from the primary tumor and BM. We also observed a decrease in primary tumor M-MDSCs and lung metastasis-associated macrophages. In summary, our preliminary clinical data suggest that GMI-1359 is well-tolerated and elicits on-target effects expected from disruption of the host microenvironment. Ongoing clinical and preclinical work will define the efficacy of this strategy to enhance responses to chemo and immune therapies. Citation Format: P. Kelly Marcom, Trevor T. Price, Andrew S. Murray, William E. Fogler, John L. Magnani, Helen Thackray, Eric Feldman, Dorothy Sipkins. Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT144.
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- 2021
23. Abstract CT026: A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER
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Alshad S. Lalani, Feng Gao, Rachel A. Freedman, Mark D. Pegram, Shana Thomas, Gretchen Kimmick, Matthew Bidwell Goetz, Julie R. Nangia, Ron Bose, Lisa A. Carey, Matthew J. Ellis, Melody A. Cobleigh, Jill Anderson, Timothy J. Pluard, Brittney Haas, Kimberly M. Hamann, Janice Lu, Jason Jones, Richard A. Bryce, Jingqin Luo, P. Kelly Marcom, Cynthia X. Ma, Frances Valdez-Albini, Nan Lin, and Eric P. Winer
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Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,Cancer ,medicine.disease ,Metastatic breast cancer ,Tolerability ,Trastuzumab ,Internal medicine ,Concomitant ,Neratinib ,medicine ,Progression-free survival ,business ,medicine.drug - Abstract
Introduction: The irreversible pan-HER inhibitor NER showed modest single agent activity for HER2mut MBC in Part I of MutHER trial. In Part II, we hypothesized that (1) N+F would improve activity in estrogen receptor positive (ER+) HER2mut MBC due to ER-HER2 crosstalk and (2) dual HER2 blockade by adding trastuzumab at disease progression (PD) could overcome resistance. Methods: Pts with ER+HER2mut MBC were enrolled to 2 cohorts (FUL treated or naive) to receive N+F with diarrhea prophylaxis. ER- pts received NER in an exploratory ER- cohort. Trastuzumab was added at PD if approved by insurance. Simon's Minimax 2-stage phase II design with the primary endpoint of clinical benefit rate (CBR: rates of complete/partial response [CR/PR] plus stable disease [SD] >24 weeks [wks]), with anticipated vs null hypothesis being CBR of 55% vs 35% (FUL treated) or 65% vs 40% (FUL naïve) with 80% power, 1 sided 0.05 alpha, was used. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Serial blood samples were analyzed for circulating tumor DNA (ctDNA) by Guardant360 for concomitant mutations, HER2mut variant allele frequency (VAF) dynamics, and resistance mechanisms. Results: Between Sep. 2015 and Oct. 2020, 40 pts with HER2mut MBC were enrolled, completing the 1st stage of each ER+ cohort. 35 pts (21 FUL treated, 10 FUL naïve, 4 ER-) were evaluable for response, with median age 63 (35-82) years, 3 (0-12) prior MBC regimen, lobular BC in 13 (37%) and visceral mets in 32 (91%) pts. 21 (68%) ER+ pts had prior CDK4/6 inhibitor. All but 1 pt has come off study due to PD. Table 1 shows the efficacy by cohort. Further enrollment is closed per protocol. Adding trastuzumab at PD induced CB in 4 (3 PR, 1 SD≥24 wks) of 5 pts (1 ER-, 4 ER+), with PFS 28 (95% CI 18~NA) wks. Common AEs across cohorts were diarrhea (G3 21%) and fatigue (G3 5%). No G4 AEs. ctDNA HER2mut was detected in 72% (23/32) baseline (BL) samples tested. In pts with paired samples, HER2mut VAF decreased at C1D15/C2D1 from BL in 75% (15/20) and rose in 89% (16/18) at PD. Acquired HER2mut, including the T798I gatekeeper mutation, were detected in 2 pts at PD. Mutations in TP53 (53%), PIK3CA (43%), and CDH1 (35%) were common, but none significantly associated with PFS in all or ER+ pts. Conclusions: NER, or N+F, is active for HER2mut MBC with good tolerability. Adding trastuzumab at PD induced further response, supporting dual HER2 blockade for HER2mut MBC. Table 1.EfficacyCohortFUL treatedFUL naïveER-Best Response, n evaluablen = 21n = 10n = 4CR, n100PR, n431SD (≥ 24 wks), n300SD (< 24 wks), n1030PD, n343CBR, n with CB/total n evaluable, % (95% CI)8 of 20*, 40% (19~64%)3 of 10, 30% (7~65%)1 of 4, 25% (0.6~81%)mPFS (95% CI), wks, ITT (n)24 (16~31) wks, (n = 24)20 (8~NA) wks, (n = 11)8.5 (8~NA) wks, (n = 5)*20 of 21 pts are evaluable for CBR in the FUL treated Cohort as 1 pt had SD as best response and treatment is still ongoing. ITT (intent to treat) population is used for mPFS estimate. Citation Format: Cynthia X. Ma, Jingqin Luo, Rachel A. Freedman, Timothy Pluard, Julie Nangia, Janice Lu, Frances Valdez-Albini, Melody Cobleigh, Jason Jones, Nancy U. Lin, Eric Winer, P. Kelly Marcom, Shana Thomas, Jill Anderson, Brittney Haas, Kimberly M. Hamann, Richard Bryce, Alshad S. Lalani, Lisa Carey, Matthew Goetz, Feng Gao, Gretchen Kimmick, Mark Pegram, Matthew J. Ellis, Ron Bose. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT026.
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- 2021
24. Abstract S2-05: Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study
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Shannon Puhalla, Agnes Jager, Mark E. Robson, Paul K. Marcom, P Bonnet, SJ Isakoff, Christine K. Ratajczak, M. Campone, Jiang Qian, Alan S. Coates, Véronique Diéras, Melinda L. Telli, Hyo S. Han, M Palácová, Q Qin, Susan M. Domchek, Michael Friedlander, Vincent L. Giranda, D Citrin, I. Bondarenko, Stacie Peacock Shepherd, and Bella Kaufman
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Veliparib ,business.industry ,medicine.medical_treatment ,Cancer ,Phases of clinical research ,medicine.disease ,Gastroenterology ,Metastatic breast cancer ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,PARP inhibitor ,medicine ,030212 general & internal medicine ,business - Abstract
Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA+ per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2-mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Table 1Efficacy (ITT population – BRCA mutation)Plc+C/P, n=98V+C/P, n=95HR (95% CI); P valuePFS(mo, 95% CI)12.3 (9.3–14.5)14.1 (11.5–16.2)0.789 (0.536–1.162); 0.231OS (mo, 95% CI)25.0 (18.1–34.8)28.5 (22.4–NR)0.725 (0.468–1.121); 0.148ORR, % (95% CI)61.3 (49.7–71.9)77.8 (66.4–86.7)P=0.027 Citation Format: Han HS, Diéras V, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-05.
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- 2017
25. Abstract PS16-06: Identification of pathogenic FGFR1, FGFR2, and FGFR3 alterations in cell-free DNA (cfDNA) from patients with metastatic breast cancer
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Benjamin Mayro, Jeremy Force, Carey K. Anders, P. Kelly Marcom, Leylah Drusbosky, Mary Love Taylor, and Robin Batchelder
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musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Mutation ,Kinase ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Metastatic breast cancer ,stomatognathic diseases ,Breast cancer ,Oncology ,Erdafitinib ,embryonic structures ,medicine ,Cancer research ,Copy-number variation ,Kinase activity - Abstract
Background: FGFR alterations are a known mechanism of resistance against breast cancer systemic therapies with higher FGFR RNA expression in breast cancer brain metastases compared to their primary tumors. While the genomic characterization of FGFR alterations has occurred from bulk breast tumors, the frequency and type of FGFR alterations in metastatic breast cancer (MBC) have not been fully characterized from cfDNA. The purpose of this study was to identify the incidence of FGFR1, FGFR2, and FGFR3 genomic alterations in cfDNA from patients with MBC and elucidate which FGFR alterations may increase FGFR kinase activity or may function as mechanisms of resistance against the FDA approved FGFR inhibitor, erdafitinib. Methods: We queried 16,053 reports from Guardant Health between June 2015 - October 2019 to identify the incidence of FGFR1, FGFR2, and FGFR3 alterations detected in cfDNA from MBC. We classified each alteration type into the following categories: copy number variation (CNV), fusion, indel, or single nucleotide variant (SNV). Focus was placed on characterizing FGFR1, FGFR2, and FGFR3 SNVs. We compared known activating mutations in EGFR, ERBB2, and BRAF with homologous regions in FGFR1, FGFR2, and FGFR3. In silico modeling with PyRx was used to dock erdafitinib onto FGFR1 (PDB 4V05), FGFR2 (PDB 5B7V), and FGFR3 (PDB 6LVM) kinases. Three-dimensional in silico analyses with ChimeraX was utilized to further determine which alterations may increase FGFR1, FGFR2, and FGFR3 kinase activity or may induce resistance against erdafitinib. Results: The incidence of nonsynonymous alterations occurring in FGFR1, 2213 (13.8%); FGFR2, 1017 (6.3%); and FGFR3, 144 (0.9%) were identified in the Guardant Health MBC database. FGFR1, FGFR2, and FGFR3 alterations are detailed in Table 1. We identified 40 (9.15%) and 167 (38.2%), 55 (7.2%) and 310 (40.4%), and 31 (27.4%) and 32 (28.3%) mutations occurring in the transmembrane/juxtamembrane and kinase domains of FGFR1, FGFR2, and FGFR3, respectively. Hotspot mutations were observed at R54C/S/G/R and N546K/D/S in FGFR1, D304N and N549K/D/S in FGFR2, and at S408/F/C/L/Y in FGFR3. We aligned FGFR1, FGFR2, and FGFR3 with homologous kinases and found 12 unique samples with mutations in our FGFR1 dataset corresponded to known activating mutations in EGFR and ERBB2; 18 samples with mutations in our FGFR2 dataset corresponded to known activating mutations in EGFR, ERBB2, and BRAF; and 1 mutation in our FGFR3 dataset corresponded to a known activating mutation in ERBB2. FGFR1 mutations C488S, V492M, M535I, L569V and FGFR2 mutations L550V, E565A, Y566N, S568C, G570R, G685E are postulated to induce resistance against erdafitinib. Conclusions: We found that 21% of MBC in this dataset harbor FGFR genomic alterations detected from cfDNA. Novel somatic alterations in FGFR1, FGFR2, and FGFR3 were identified from Guardant Health that were not detected in the public domain. A portion of FGFR SNVs occurred at known homologous kinase activating mutations in EGFR, ERBB2, and BRAF suggesting these specific FGFR mutations may increase FGFR kinase activity and might be actionable therapeutic targets in breast cancers harboring these mutations. Three dimensional analyses of the FGFR protein tyrosine kinase further illustrate which specific alterations may increase FGFR kinase activity or induce resistance against erdafitinib. Table 1. Incidence and type of FGFR alterations in Guardant Health MBC databaseGeneCNV (%)Fusion (%)Indel (%)SNV (%)FGFR11770 (80%)-6 (0.3%)437 (19.7%)FGFR2224 (22%)15 (1.5%)11 (1.1%)767 (75.4%)FGFR3-24 (16.7%)7 (4.9%)113 (78.4%) Citation Format: Mary Love Taylor, Benjamin Mayro, Leylah Drusbosky, Robin Batchelder, P. Kelly Marcom, Carey Anders, Jeremy Force. Identification of pathogenic FGFR1, FGFR2, and FGFR3 alterations in cell-free DNA (cfDNA) from patients with metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-06.
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- 2021
26. Abstract P2-04-19: Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients
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Paul K. Marcom, S Hwang, Kent J. Weinhold, Gloria Broadwater, Jeremy Force, Terry Hyslop, Edgardo R. Parrilla Castellar, Smita K. Nair, Sara Abbott, Kelly E. Westbrook, K. L. Blackwell, Noah D. Kauff, Ilona Stashko, and Gretchen Kimmick
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Oncology ,Cancer Research ,medicine.medical_specialty ,animal structures ,endocrine system diseases ,business.industry ,BRCA mutation ,Microsatellite instability ,Cancer ,Gene mutation ,medicine.disease ,female genital diseases and pregnancy complications ,Breast cancer ,Internal medicine ,medicine ,Gastrointestinal cancer ,Stromal tumor ,skin and connective tissue diseases ,business ,Triple-negative breast cancer - Abstract
Background: Increased stromal tumor infiltrating lymphocytes (TILs) are predictive and prognostic for improved outcomes from neoadjuvant or adjuvant chemotherapy in triple negative breast cancer. Increased tumor mutational burden may promote neoantigens causing immune system upregulation. Microsatellite instability in gastrointestinal cancer predicts for response to checkpoint inhibition and is associated with inherited cancer predisposition. The immune system response in BRCA mutated breast cancer has not been described. The purpose of this study is to assess tumor infiltrating immune cells in early stage breast cancer patients with and without BRCA gene mutations. Methods: We retrospectively investigated 124 early stage breast cancer patients with BRCA mutations (n=62, BRCA+) and without BRCA mutations (n=62, BRCA WT). The %TILs was measured manually by H&E. Our control group consisted of age, stage, and receptor status matched early stage untreated breast cancer patients who were deemed BRCA WT by extended gene panel testing or were negative for BRCA 1/2 and had a posttest probability of harboring an autosomal dominant mutated gene of ≤ 1% using the Bayes-Mendel algorithm. We used a two-sample binomial arcsin approximation to detect a 20% difference in TILs between cohorts to attain 80% power with a one-side alpha of 0.05. Wilcoxon Rank-Sums test was used to compare differences in the central tendencies for continuous variables. We used the Nanostring PanCancer immune profiling panel to immunophenotype a portion of the BRCA+ and BRCA WT cohorts and used nSolver for quality control, normalization, and bioinformatics analyses. Results: Here we report TILs from the first 21 patients of our study. Thirteen patients harbored BRCA mutations and eight patients did not. All patients were HER2 negative. Eight (61%) and four (50%) patients were hormone receptor positive (HR+) in the BRCA+ and BRCA WT cohorts, respectively. Median %TILs were not significantly different between the BRCA+ (15, range 0-70) and BRCA WT (17.5, range 5-60; p=0.7) groups. Median %TILs in the HR+/BRCA+ (12.5, range 0-50) and HR-/BRCA+ (15, range 5-70) cohorts were not statistically different when compared to HR+/BRCA WT (10, range 5-15; p=0.4) and HR-/BRCA WT (30, range 20-60; p=0.2) cohorts, respectively. There were 2 patients with lymphocyte predominant breast cancer (n=1, HR-/BRCA+; n=1, HR-/BRCA WT). Conclusions: This is the first study to characterize TILs and a tumor immune microenvironment phenotype in early stage breast cancer patients with BRCA mutations. These results suggest harboring a BRCA mutation is not associated with increased TILs in early stage untreated breast cancer patients. This conclusion stayed true regardless of hormone receptor status. However, a trend of decreased TILs was seen in HR-/BRCA+ patients when compared to those with HR-/BRCA WT disease. Moreover, the median and range of TILs were higher in the HR+/BRCA+ group compared to the HR+/BRCA WT group. This suggests increased TILs may exist in some HR+ patients with a BRCA mutation. Further investigation of TILs and immune profiling of early stage untreated breast cancer patients with and without BRCA mutations is warranted. Citation Format: Force J, Abbott S, Broadwater G, Kimmick G, Westbrook K, Hwang S, Kauff N, Stashko I, Weinhold K, Nair S, Hyslop T, Blackwell K, Castellar E, Marcom PK. Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-19.
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- 2017
27. Abstract GS6-03: Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031)
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Nadine Tung, Ian E. Krop, Banu Arun, Eric P. Winer, Virginia F. Borges, Erica L. Mayer, Paul K. Marcom, Andrew J. Goss, E Hofstatter, Steven J. Isakoff, Robert D. Legare, Claudine Isaacs, Michele R. Hacker, Paulina B. Lange, Deborah Toppmeyer, Stuart J. Schnitt, Judy Garber, and Antonio C. Wolff
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,BRCA mutation ,Estrogen receptor ,Phases of clinical research ,Cancer ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adjuvant therapy ,skin and connective tissue diseases ,business ,medicine.drug - Abstract
Background: Single-agent platinum compounds have significant clinical activity in the neoadjuvant and metastatic settings for triple-negative breast cancer (TNBC) in BRCA mutation carriers. Limited data exist regarding activity in estrogen receptor (ER)-positive breast cancer among BRCA carriers. The INFORM trial is an investigator-initiated, randomized, multicenter, phase II study comparing pathologic complete response (pCR) rates with neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin/cyclophosphamide (AC) in BRCA carriers with newly-diagnosed Stage I-III HER2-negative breast cancer. Methods: BRCA carriers with cT1-3 (≥1.5 cm), cN0-3 HER2-negative breast cancer were randomized (stratified by site and ER status) 1:1 to preoperative CDDP (75mg/m2 every 3 wks x 4) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 wks x 4) followed by surgery. Prior chemotherapy was not allowed; subsequent adjuvant therapy was selected by treating clinicians. Baseline tumor features and pathologic responses were centrally determined. The primary endpoint was pCR (ypT0/is, N0). Based on a 2-sided α=0.1, a sample size of 170 provided 80% power to detect an improvement in pCR from 30% with AC to 50% with CDDP. Slow accrual led to early trial closure. We used an intent-to-treat approach and log-binomial regression to calculate risk ratios (95% confidence intervals (CI)), adjusting for ER status. Results: We randomized 118 patients; 117 were included in outcome analyses. The mean age was 42 years (range: 24-73); 69% were BRCA1+, 30% BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% of patients had nodal involvement at baseline. Most patients (70%) had TNBC (ER/PR Table 1: Intention-to-treat analysis comparing CDDP to ACCDDP n=60 n (%)AC* n=57 n (%)Crude Risk Ratio (95% CI)Adjusted Risk Ratio§ (95% CI)Pathologic complete responseResidual cancer burden score: 0All participants11 (18)15 (26)0.70 (0.35-1.4)0.67 (0.35-1.3)Triple negative (ER and PR Conclusion: While CDDP has single-agent activity in BRCA carriers with HER2-negative breast cancer, the pCR rate with CDDP is not higher than with standard AC chemotherapy. CDDP activity was notably lower in BRCA carriers with hormone-receptor positive breast cancer, though the sample size was small. Study-collected tumor and blood samples are being analyzed for biomarkers of response. Clinical information: NCT01670500. Funding: Breast Cancer Research Foundation; Susan G. Komen for the Cure; Myriad Genetics, Inc. Citation Format: Nadine Tung, Banu Arun, Erin Hofstatter, Michele R. Hacker, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul K. Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber. Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-03.
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- 2020
28. Abstract P1-06-04: Small-molecule screening nominates diverse combination therapies that sensitize BRCA mutant and wild-type triple negative breast cancer to PARP inhibition
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Sammons, S, primary, Yip, C, additional, Anderson, G, additional, Force, J, additional, Marcom, K, additional, Westbrook, K, additional, Anders, CK, additional, Blackwell, K, additional, and Wood, K, additional
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- 2019
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29. Abstract P3-08-07: Distinct biological signatures describe differences in BRCA mutated subgroups
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Force, J, primary, Plichta, J, additional, Stashko, I, additional, Kimmick, G, additional, Westbrook, K, additional, Sammons, S, additional, Hwang, S, additional, Hyslop, T, additional, Kauff, N, additional, Castellar, E, additional, Nair, S, additional, Weinhold, K, additional, Davis, S, additional, Mashadi-Hossein, A, additional, Brauer, HA, additional, and Marcom, PK, additional
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- 2019
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30. Abstract P5-15-11: The distress screening tool: Initial experience with electronically curated patient reported measures
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Kelly Marcom, Gretchen Kimmick, Janet K. Horton, Kimberly L. Blackwell, Steve Power, Rachel A. Greenup, Shelley Hwang, Heather Sperling, Rachel C. Blitzblau, Kellly Westbrook, Jeffrey Peppercorn, and Ilona Stashko
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Gerontology ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,medicine.disease ,Checklist ,Distress ,Breast cancer ,Oncology ,Quality of life ,Cohort ,medicine ,Stage (cooking) ,business ,education ,Psychosocial - Abstract
Background: In June 2013, our health system transitioned to an electronic medical record (EMR) which included collecting patient quality of life data at each clinic visit. We used the NCCN distress thermometer (DT), a short, simple to use, self-report measure which uses a 10-point scale from 0 (no distress) to 10 (extreme distress) as well as an associated problem checklist which queries the source(s) of their distress. Among our breast cancer clinic population, we studied the severity and sources of distress as well as whether the DT score was associated with stage at diagnosis and time interval since diagnosis. Methods: Between October 1, 2013 and April 30, 2014, starting 3 months after implementation of a comprehensive EMR, all patients seen at our tertiary breast cancer clinic were asked to complete the DT survey at each clinic visit. DT data were collected and entered into the EMR at point of care. The DT tool was correlated with demographic and tumor information from our prospectively curated electronic datamart. Results: We collected 7276 DT surveys from 3267 unique patients over seven months. Median age of the cohort was 60 years; 73% were white and 21% were black. Among those with available staging data and a diagnosis of breast cancer, stage distribution was 10% stage 0, 34% stage I, 37% stage II, 15% stage III and 4% stage IV. The median reported distress score was 1.0 (range 0-10) with score distribution shown in Figure 1. The most commonly reported source of stress was fatigue (8.0%) followed by pain (6.8%). For new patient appointments the most commonly reported sources were worry (9.5%) followed by nervousness (8.0%). There was no significant correlation between overall distress score and stage at diagnosis. Among patients who were seen more than once during the study interval, the DT score changed for 33.7% of patients. The lowest distress scores were reported among women >3 years from initial diagnosis. Conclusions: The transition to an integrated EMR system has allowed collection of analyzable patient reported data to inform medical and psychosocial intervention. Structured data collection at point of care allows for efficient identification of and management for the major sources of distress among patients during breast cancer treatment and survivorship. Citation Format: Shelley Hwang, Steve Power, Ilona Stashko, Rachel Blitzblau, Rachel Greenup, Janet Horton, Kellly Westbrook, Kimberly Blackwell, Heather Sperling, Jeffrey Peppercorn, Gretchen Kimmick, Kelly Marcom. The distress screening tool: Initial experience with electronically curated patient reported measures [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-11.
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- 2015
31. Abstract S1-04: A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC)
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Denise A. Yardley, Ian E. Krop, KS Albain, HJ Burstein, Beth Overmoyer, Lisa A. Carey, William T. Barry, Paul K. Marcom, Chau T. Dang, Beverly Moy, MJ Ellis, Antonio C. Wolff, Hao Guo, Sara M. Tolaney, EP Winer, HS Rugo, AH Partridge, Clifford A. Hudis, and Iuliana Shapira
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Micrometastasis ,Phases of clinical research ,Cancer ,Neutropenia ,medicine.disease ,Gastroenterology ,Surgery ,Regimen ,Breast cancer ,Oncology ,Internal medicine ,medicine ,Adjuvant therapy ,business - Abstract
Background: Four large randomized phase III trials have reported significant improvements in disease-free (DFS) and overall survival for H administered with adjuvant polychemotherapy for HER2-positive high-risk BC. With the success of HER2-targeting, limiting chemotherapy is both reasonable and feasible, particularly for smaller, node-negative tumors. However data are limited. Methods: APT is a single arm three-stage, multicenter, phase II study of TH. Patients (pts) with HER2-positive BC (IHC 3 + and/or FISH amplified at > 2.0) with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size < 3 cm were eligible. Pts received T (80 mg/m2) with H (4 mg/kg load ®2 mg/kg) x 12 weekly (w), followed by H x 39 w (2 mg/kg weekly or 6 mg/kg q 3 w). The primary endpoint was DFS. DFS events included invasive local, regional or distant recurrence, contralateral invasive breast cancer and death from any cause. The study had 95% power to distinguish between 3-year failure rates of 9.2% vs. 5% using a Poisson model based on the total patient-years of follow-up (PYFU). Planned interim analyses were designed to stop early for futility at 225 and 800 PYFU, and the regimen would be deemed worthy of further study with Results: 410 pts were enrolled from September 2007 to September 2010 and 406 began protocol therapy. The median age was 55 (range 24-85 years). Sixty-three percent had ER+ tumors. Three percent of tumors were T1mi; T1a; 20% T1b; 41% T1c, and 9% T2 ≤ 3cm. Six pts had a nodal micrometastasis. 356 pts (88%) completed all 52 wks of therapy, with 24 and 6 pts discontinuing due to protocol-specified or other toxicities, respectively. 358 (89%) completed all 12 weeks of combined TH therapy. The most common grade 3/4 toxicities included: neuropathy (4%), neutropenia (4%), transaminitis (3%), leukopenia (2%), fatigue (2%), and hypersensitivity reactions (2%). Reversible symptomatic CHF (grade 3 left ventricular systolic dysfunction) occurred in 2 patients (0.5%). Because of the limited number of events, the Data Safety Monitoring Board approved release of study results with 1316 PYFU and a median follow-up of 3.2 years. A total of 8 DFS events have been observed: 2 pts with metastatic disease, 2 with ipsilateral axillary recurrences, 3 with new contralateral BC (all HER2-), and 1 patient who died after diagnosis of primary ovarian cancer. Conclusion: This represents the first report of TH as adjuvant therapy for node-negative HER2-positive BC. The regimen appears well tolerated and few recurrences have been observed in the study population to date. An updated analysis of efficacy, including estimates of 3-year DFS, will be presented in December when a total of 1520 PYFU in this cohort is anticipated. Based on these early data, the TH regimen may be an acceptable treatment approach for low risk HER2-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-04.
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- 2013
32. Abstract P3-08-05: Chemotherapy-related amenorrhea on adjuvant paclitaxel-trastuzumab (APT trial)
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Denise A. Yardley, Beverly Moy, HS Rugo, Kathryn J. Ruddy, Iuliana Shapira, Clifford A. Hudis, Chau T. Dang, Lisa A. Carey, Sara M. Tolaney, Antonio C. Wolff, Ian E. Krop, KS Albain, HJ Burstein, AH Partridge, Beth Overmoyer, MJ Ellis, Hao Guo, EP Winer, and Paul K. Marcom
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Gynecology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Taxane ,Aromatase inhibitor ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Regimen ,Breast cancer ,Breast cancer chemotherapy ,Internal medicine ,medicine ,Amenorrhea ,medicine.symptom ,skin and connective tissue diseases ,business ,Tamoxifen ,medicine.drug - Abstract
Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. The majority of premenopausal women experience prolonged CRA (persisting for at least a year after chemotherapy has finished) with standard adjuvant breast cancer chemotherapy regimens. Trastuzumab is not believed to cause CRA. No studies to date have evaluated the risk of CRA from a taxane in the absence of other gonadotoxic therapy. If the paclitaxel-trastuzumab regimen is adopted for treatment of women with low to moderate risk Her2+ breast cancer, understanding its impact on this important survivorship issue will be of great interest. Methods: 410 patients enrolled on a single-arm phase 2 adjuvant chemotherapy study of 12 weeks of paclitaxel-trastuzumab followed by nine months of trastuzumab monotherapy for patients with Results: Seventy-seven participants in the APT trial were premenopausal at enrollment, of whom 12 (16%) did not have follow-up menstrual data at least 15 months after their first dose of chemotherapy. In the remaining 65, median age was 44 years (range 27-52), and 59 (91%) were white. Forty-two (65%) had ER+ disease. Thirty-three (51%) were taking tamoxifen and 3 (7%) were taking an aromatase inhibitor when they completed their most recent menstrual surveys. The median time between first dose of chemotherapy and the last available menstrual survey was 40 months (range 17-63 months). At the time of their last available menstrual survey, 19 (29%) were amenorrheic and 46 (71%) were not amenorrheic. Conclusions: Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel-trastuzumab for early stage breast cancer appear lower than would have been expected with standard adjuvant cytotoxic breast cancer regimens (most studies of various standard regimens have found CRA rates of at least 50%). Additional follow-up and analyses are planned to clarify how menstrual functioning changes over time after paclitaxel-trastuzumab. Future studies are also needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms in young women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-05.
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- 2013
33. Abstract P2-16-13: Phase I dose escalation clinical trial of the PI3K inhibitor BKM120 and capecitabine (C) in metastatic breast cancer (MBC)
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Carey K. Anders, KE Reeder-Hayes, D Rosenstein, J Noe, Anna C. Snavely, Lisa A. Carey, Paul K. Marcom, CM Perou, K. L. Blackwell, Gretchen Kimmick, and Elizabeth Claire Dees
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,Nausea ,medicine.medical_treatment ,Cancer ,Pharmacology ,medicine.disease ,Gastroenterology ,Rash ,Metastatic breast cancer ,Capecitabine ,Oncology ,Internal medicine ,Mucositis ,Medicine ,medicine.symptom ,business ,Adverse effect ,medicine.drug - Abstract
Background: PIK3CA is one of the most frequently mutated genes in human breast cancer, and the high expression of a PIK3CA-pathway signature is associated with the poor prognosis Luminal B and Basal-like expression subtypes. BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which has shown activity in preclinical and early clinical testing, and synergy with both endocrine and chemotherapy. In this trial we sought to evaluate the safety and estimate the maximum tolerated dose (MTD) of the combination of BKM120 and C in patients (pts) with MBC. Methods: In a 3+3 dose escalation design, we evaluated four cohorts of BKM 120 daily plus C BID x 14 days in 21 day cycles. Standard definitions for DLT and MTD were used and evaluated on the first cycle. Toxicity was graded by CTCAE version 4. Response was evaluated after 2 cycles by RECIST criteria. Pts with MBC appropriate for treatment with C who had Results: 21 pts (11 hormone receptor (HR)+, 3 HER2+, 9 HR/HER2-negative) were enrolled and treated. All were evaluable for toxicity and 14 for response to date. Median age was 54 (range 35-65). Median prior chemotherapy regimens for MBC was 2 (range 1-4). The following dose levels (DL) were evaluated: BKM120 50 mg/d + C 1000 mg/m2/BID x 14(DL 1-4 pts), BKM120 80 mg/d + C 1000 mg/m2/BID x 14 (DL2-3 pts), BKM120 100 mg/d + C 1000 mg/m2/BID x 14 (DL3-9 pts), BKM120 100 mg/d + C 1250 mg/m2/BID x 14 (DL4-5 pts). Most frequent adverse events (all grades) included: Nausea (12), mood disorders (11), PPE (9), diarrhea (8), fatigue (7), vomiting (5) mucositis (4), rash (4), photosensitivity (3), hyperglycemia (3). Grade 3 or higher AEs in any cycle were transaminitis (3) diarrhea (2) mood disorder (2), hyperglycemia, fatigue, photosensitivity, PPE (1 pt each). DLTs: grade 3 hyperglycemia (1/6 pts at DL3), and grade 3 mood disorder in 1/5 pts DL 4. Additionally 4 of 5 patients at DL 4 required dose reduction or delay prior to C3D1. Thus DL 4 exceeded the MTD and DL 3 was expanded for further safety evaluation. Antitumor activity was seen with best responses of 1 CR (at DL 3), 3 PR (DL1 and 4) and 7 SD. PK analysis, assessment of tumor PIK3CA mutation status and intrinsic subtype by PAM50 is ongoing. Conclusions: The combination of BKM120 100 mg po q day and C 1000 mg/m2 / BID x 14 d in 21 day cycles is tolerable and appears active. PK and biomarker analysis are ongoing. A phase II trial is planned. Acknowledgements: This study was funded by Novartis Pharmaceuticals and by a grant from Susan G. Komen for the Cure (SAC 110044). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-13.
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- 2013
34. Abstract PD3-01: Immune profile of small HER2+ tumors in the APT trial
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Tolaney, SM, primary, Barry, W, additional, Guo, H, additional, Dillon, D, additional, Tan, YB, additional, Fuhrman, K, additional, Osmani, W, additional, Getz, A, additional, Baltay, M, additional, Dang, C, additional, Yardley, D, additional, Moy, B, additional, Marcom, K, additional, Krop, I, additional, and Winer, E, additional
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- 2018
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35. Abstract P4-09-01: Retrospective evaluation of precision of gene-expression-based signatures of prognosis and tumor biology in replicate surgical biospecimens from patients with breast cancer
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Michael B. Datto, Joseph Geradts, William T. Barry, and Paul K. Marcom
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,Intraclass correlation ,business.industry ,Concordance ,Cancer ,Replicate ,Bioinformatics ,medicine.disease ,Confidence interval ,Breast cancer ,MammaPrint ,Internal medicine ,medicine ,Biomarker (medicine) ,business - Abstract
Background: Numerous gene-expression signatures have been developed for breast cancer. However, assessments of their validity continue to largely ignore the impact of intratumor heterogeneity and technical variation on clinical utility. Here, the collection of replicate specimen in Barry et al (2010) is used to evaluate a broad collection of gene-expression signatures of prognosis and tumor biology. Methods: Eighteen patients with multiple frozen cores (one patient with quadruplicate, twelve with triplicate, and five with doublet samples) were previously identified in the Duke Breast SPORE tissue repository. Cores were assessed for percent invasive cancer cellularity, and tumor size, grade, and ER/PR status. RNA was extracted and hybridized to AffymetrixH133Plus2.0 microarrays. Expression signatures of prognosis and tumor biology were developed or translated to the Affymetrix platform using routines by Prat et al. (2012) and Haibe-Keins et al. (2012). Association between signatures, and precision among replicates are evaluated using Pearson and intraclass correlation. Coefficients are reported with 95% confidence intervals. Results: Among prognostic signatures, an imputed 70-gene signature of MammaPrint had the highest level of precision (ICC = 0.96, 0.91–0.98); strong concordance is seen with Affymetrix-based PAM50 risk-of-relapse (ICC = 0.82, 0.65–0.92); 16 of 18 patients had constant subtype calls. Substantially lower concordance was seen in the GENIUS prognostic model (ICC = 0.62, 0.35–0.82). In ER+ patients (n = 13), two algorithms to impute the 21-gene model of OncotypeDX recurrence score were concordant (r = 0.98, ICC= 0.90 and 0.83) and distinct from the GENIUS ER+ score (average r = 0.74, ICC=0.78). Imputed models for the Rotterdam 76-gene model (+ER status), GGI (+grade), and ROR-T (+tumor size) showed lower levels of correlation (0.47 Conclusions: The number of genomic signatures in breast cancer from archived specimen and cell-line experiments continues to grow, but there are limited resources for validating their prognostic/predictive value in patient populations. Reproducibility across biological replicates is a critical component in establishing clinical utility of a signature that is distinct from using technical replicates for the repeatability of analytes on the array platform. We demonstrate how archived specimen can confirm reproducibility in the ‘Test Validation Phase’ of biomarker development, as advocated by the Institute of Medicine, and inform trial designs to prospectively test clinical utility. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-01.
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- 2012
36. Abstract P4-13-06: Association of Age, Obesity and Incident Breast Cancer Phenotypes
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Kelly Marcom, R Scheri, Victoria L. Seewaldt, Steve Power, S Hwang, and Jeffrey R. Marks
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Cancer Research ,medicine.medical_specialty ,business.industry ,Insulin ,medicine.medical_treatment ,Cancer ,medicine.disease ,Phenotype ,Gastroenterology ,Obesity ,Breast cancer ,Endocrinology ,Oncology ,Tumor progression ,Hormone receptor ,Internal medicine ,Cohort ,medicine ,business - Abstract
Background: Obesity has been shown to be associated with increased risk of breast cancer in postmenopausal women. However, it is unclear whether this risk is isolated to a specific phenotype. We hypothesized that the increased levels of insulin, IGF-1 and estrogens associated with obesity preferentially drive an increased proportion of the luminal A phenotype of breast cancer. Methods: Between 2008 and 2011, 1001 women were diagnosed with invasive breast cancer at Duke University Medical Center and had weight and height recorded at the time of diagnosis. Tumor phenotypes were based on hormone receptor (HR: ER− and/or PR-positive) and Her2 testing with subtypes defined as follows: Luminal A: HR(+), Her2(−); Luminal B: HR(+), Her2(−); Her2: HR(−), Her2(+); triple negative: HR(−), Her2(−). Results: Median age of the cohort was 55.7 years; median BMI was 27.7. As expected, increasing BMI was associated with older age, with BMI almost evenly distributed between three groups: ≤ 25, 25–30, and >30. In the overall group, proportion of luminal B, Her2, and triple negative subtypes did not differ by BMI; however the proportion of patients with luminal A cancer increased from 65% for the lowest BMI group to 70% for the highest BMI group. Analysis stratified by age ≤ 40, 40 to 59, and ≥60 years showed a lower proportion of the triple-negative (19% vs. 6% vs. 4%, p < 0.001) and higher proportion of the luminal A (11% vs. 23% vs. 32%; p < 0.001) phenotype with older age group. This finding was limited to women with higher BMI only. Conclusions: Although there were no trends observed between BMI and incident phenotype in the overall cohort, age stratified analysis revealed striking correlations. High BMI was associated with triple negative phenotype in the youngest age group and luminal A phenotype in older age groups. These results suggest that obesity likely exerts different effects on tumor progression based on patient age and/or menopausal status. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-06.
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- 2012
37. Abstract P3-06-07: Ki67 as a Predictive Marker of Response to Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer (ESBC): A Systematic Review and Evidence Summary
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Paul K. Marcom, Amy P. Abernethy, S Hwang, Gary H. Lyman, Adane Fekadu Wogu, Geoffrey S. Ginsburg, Neal Ready, William T. Barry, Nicole M. Kuderer, Poniewierski, Eva Culakova, and Joseph Geradts
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Oncology ,Cancer Research ,medicine.medical_specialty ,Funnel plot ,Predictive marker ,business.industry ,medicine.medical_treatment ,Cancer ,Publication bias ,Odds ratio ,medicine.disease ,Breast cancer ,Internal medicine ,Medicine ,Stage (cooking) ,business ,Neoadjuvant therapy - Abstract
Background: Immunohistochemical (IHC) assessment of the proportion of cells staining for the KI67 nuclear antigen is being increasing utilized in the management of patients with early-stage breast cancer (ESBC). A comprehensive systematic review and evidence synthesis of biomarkers potentially predictive of response to systemic therapy was initiated as a part of an NCI-funded comparative effectiveness research program. Methods: Studies of chemotherapy response prediction based on baseline IHC assessment of Ki67 in patients with ESBC receiving neoadjuvant systemic therapy were identified. Response was specified as pathologic complete response (pCR) or clinical response (ClinR). Assay predictive performance for response was assessed on the basis of sensitivity, specificity, predictive value and predictive odds ratio (POR±95%CLs) utilizing mixed effects models. Study results were fitted in an ROC analysis based on the method of DerSimonian and Laird. Publication bias was evaluated on the basis of funnel plot asymmetry assessed by Egger's regression intercept and Begg and Mazumdar's rank correlation. Results: Of 469 potentially eligible studies, dual blind full text review identified 42 eligible studies reporting 44 independent cohorts with 6,716 patients (21–979). While Ki67 cutpoints varied considerably, they were most commonly between 10%–30% (median 20%, range 1–50%). The analysis prsented here is limited to the 30 studies of ESBC patients (N = 3,343) receiving neoadjuvant therapy of which 14 reported fewer than 100 patients. The proportion of patients with elevated Ki67 across studies ranged from 0.20–0.92 (median = 0.54). Sensitivity and specificity for treatment response in patients with high vs. low baseline Ki67 was 0.65 [0.61, 0.68] and 0.52 [0.50, 0.54], respectively. Estimated response rates across studies in patients with high vs. low Ki67 were 31% [29%, 34%] and 19% [17%, 21%], respectively. The estimated POR for response across studies was 2.82 [2.14, 3.72; P < .001]. POR was significantly greater in studies of anthracycline-based [3.0] than non-anthracycline regimens [0.92](Pinteraction = .043) and of cyclophosphamide-based [3.41] compared to non-cyclophosphamide regimens [2.00](P interaction=.039) but was not associated with treatment based on other drug classes. Although Ki67 predictive performance was not significantly associated with the cutpoint utilized or the proportion of patients with ER or PR+, Her2+, or high grade tumors across studies, analysis based on individual patient data is needed to assess performance in specific clinical subgroups. No significant publication bias was found. Conclusions: A compelling need exists for larger studies with greater methodologic rigor and standardization to assess the clinical validity of Ki67 in ESBC as well its clinical utility in guiding neoadjuvant treatment decisions compared to the use of conventional predictive markers. Funding: NCI: RC2CA14041-01 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-07.
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- 2012
38. Abstract P1-13-05: The association between timing in adjuvant chemotherapy administration and overall survival for women with breast cancer within the National Comprehensive Cancer Network (NCCN)
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Y-N Wong, Tara M. Breslin, Antonio C. Wolff, Stephen B. Edge, Joyce C. Niland, Rebecca A. Ottesen, Jane C. Weeks, John L. Wilson, Beverly Moy, JL Vandergrift, HS Rugo, and Paul K. Marcom
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Oncology ,Gynecology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,Pathological staging ,medicine.medical_treatment ,Cancer ,medicine.disease ,Comorbidity ,Breast cancer ,Internal medicine ,medicine ,T-stage ,Stage (cooking) ,business ,Neoadjuvant therapy - Abstract
Introduction: Population based studies (eg, Hershman et al. BCRT 2006 and Lohrisch et al. JCO 2006) showed poorer survival associated with long delays in adjuvant chemotherapy (CTX) initiation following definitive surgery (DS) for women with breast cancer (BC). Delays in CTX following diagnosis (DX) have not been evaluated. The ASCO/NCCN quality measures (QMs) recommend CTX Methods: 4,608 women with stage I-III HER2 negative breast cancer diagnosed between 2000 and 2006 at 8 NCCN centers were identified using the NCCN outcomes database. Patients with T3/4 disease or who received neoadjuvant therapy were excluded. The association between CTX timing and OS was evaluated using multivariate Cox models adjusted for CTX type, age, race, BMI, residential distance, insurance, SES, comorbidity, ER/PR, LVI, grade, T stage, and N stage. The impact of CTX timing was evaluated using a >90-day (d) DS-to-CTX threshold, based on poor outcomes observed in prior studies, and a >120d DX-to-CTX threshold, based on the ASCO/NCCN QMs. Results: Median follow-up was 7.2 years and OS at 7 years was 89%. Overall, 401 (8.7%) patients received CTX >120d after DX and 113 (2.4%) patients received CTX >90d after DS. The DX-to-CTX interval was more strongly correlated with the DX-to-DS (r = 0.74) interval than DS-to-CTX (r = 0.54) interval. A >90d DS-to-CTX interval was significantly associated with poorer survival (HR: 1.65, 95% CI 1.04–2.60, p = 0.03) in adjusted analyses. Shorter DS-to-CTX thresholds of >60d (n = 636, HR: 1.13, 95% CI: 0.89–1.43, p = 0.319) or >75d (n = 273, HR: 1.05, 95% CI 0.74–1.49, p = 0.76) were not associated with OS. The association between a >120d DX-to-CTX interval and OS was not statistically significant (HR: 1.32, 95% CI 0.99–1.76, p = 0.06). Patients who received CTX >135d (n = 231, HR 1.25, 95% CI: 0.87–1.81, p = 0.22) or >150d (n = 128, HR 1.15, 95% CI: 0.59–2.24, p = 0.69) after DX did not display an increased risk of death. Excluding pathological staging factors from the model had no effect on the results. In subgroup analyses stratified by ER/PR, LVI, grade, T stage or N stage, a >120d delay in CTX did not display significant associations with OS. Among ER/PR negative patients, the association between a >120d delay and OS was borderline non-significant after adjusting the p-value for multiple hypothesis testing using the false discovery rate method (HR: 1.80, 95% CI: 1.16–2.79, p = 0.09). Conclusion: Consistent with previous studies, CTX delays of >90 days following surgery were associated with poorer survival. OS was not significantly compromised in patients with DX-to-CTX intervals >120 days although this analysis may have limited power to detect small effects. More variation in the DX-to-CTX interval was attributed to pre-surgery time which may explain the differences observed between the DX-to-CTX and DS-to-CTX intervals. Among patients with ER/PR negative disease, a non-significant association between OS and a >120 day DX-to-CTX interval was observed that warrants further examination. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-05.
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- 2012
39. Abstract P2-10-03: A cross-platform comparison of genomic signatures and OncotypeDx score to discover potential prognostic/predictive genes and pathways
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Neal Ready, Michael B. Datto, Nicole M. Kuderer, S Hwang, P Isner, Gary H. Lyman, Paul K. Marcom, P Agarwal, Geoffrey S. Ginsburg, William T. Barry, Timothy Veldman, Joseph Geradts, and V Liotcheva
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False discovery rate ,Cancer Research ,Microarray ,medicine.diagnostic_test ,business.industry ,Cancer ,Context (language use) ,medicine.disease ,Bioinformatics ,Breast cancer ,Oncology ,MammaPrint ,Multiple comparisons problem ,Medicine ,KEGG ,business - Abstract
Background: Microarray assessment of breast cancer demonstrates disease subsets among the major breast cancer biologic categories (ER, PR, HER-2) with likely additional prognostic and treatment (predictive) implications. Additional prognostic and predictive biomarkers and optimization of existing genomic platforms are needed to improve personalized breast cancer care. Methods: 76 early-stage ER+ patients with adequate RNA from fresh frozen tumor specimens and a concurrent 21-gene OncotypeDX recurrence score (RS) were identified across independent Duke studies linked to routine prospective breast biospecimen collection. Expression estimates for Affymetrix H133 Plus 2.0 microarrays were reviewed for quality control (Owzar 2008) and normalized across 4 batches with ComBat. Correlations of genomic prognostic signatures to true RS were assessed using Spearman coefficients. Discovery of new gene-level and pathway-level associations to breast cancer prognosis and prediction, based on RS, were corrected for multiple comparisons using the Bonferonni for the family-wise error rate (FWER) or Benjamini-Hochberg methods for the false discovery rate (FDR). Results: A total of 73 samples passed Affymetrix quality control: 32 “low risk”, 32 “intermediate risk”, and 9 “high risk” using standard recurrence score thresholds of 30. Median patient age is 55 (range 35–86). Two published algorithms to impute the RS from the Affymetrix model by Fan and Haibe-Keins were highly concordant (94%) with each other and showed strong correlation to actual RS (rho = 0.62, p = 5e−9). However, when the RS thresholds were applied to the microarray-based scores, lower agreement was observed (misclassification rate of 57%). Strong correlation was also observed with other breast signatures and RS, including an imputed 70-gene signature of MammaPrint (rho = 0.59, p = 3e−8) and the 50-gene PAM50 risk-of-relapse score (rho = 0.54, p = 8e−7), while poor correlation was seen for the GENIUS prognostic model (rho = 0.06, p = 0.6). Discovery of gene-level associations to RS identified 28 genes, including known cancer-associated genes such as BRCA2 (FWER adj p = 0.002), Cyclin E1 (FWER adj p = 0.015), and CDCA5 (FWER adj p = 0.048). Pathway-level association in KEGG and GO Biologic Processes, identified 24 and 104 categories respectively, including Cell Cycle pathways KEGG:04110 (FDR adj p = 0.002) and GO:0000085 (FDR adj p = 0.0007). Among 22 in-vitro derived oncogenic pathway signatures, significant negative correlation is seen with p53 (rho = −0.56, adj p = 4e−6) and positive correlation with beta-catenin (rho = 0.38, adj p = 0.015). A multi-gene model of association to OncotypeDX RS classification is being developed using Prediction Analysis of Microarrays (PAM). Conclusions: Microarray-based prognostic breast cancer signatures are generally concordant. However, their application across platforms is currently sub-optimal. In the context of OncotypeDX RS, additional key cancer-associated genes and pathways are found to be associated with breast cancer prognosis, potentially providing insight into treatment opportunities for ER+ breast cancer. Validation efforts of these findings in an independent patient cohort are underway. Funding: NCI: RC2CA14041-01 and W81XWH-07-1-0394 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-03.
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- 2012
40. P2-18-02: Cardiac Outcomes of Patients on Adjuvant Weekly Paclitaxel (T) and Trastuzumab (H) for Node Negative, HER2 Positive Breast Cancer (BCA)
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Kelly Marcom, Chau T. Dang, Julie Najita, Denise A. Yardley, Ian E. Krop, KS Albain, Kathy D. Miller, Sara M. Tolaney, HS Rugo, MJ Ellis, Iuliana Shapira, Clifford A. Hudis, Linda T. Vahdat, EP Winer, HJ Burstein, Antonio C. Wolff, Lisa A. Carey, S Burdette-Radoux, T Budd, and Rebecca Gelman
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Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Ejection fraction ,Taxane ,Anthracycline ,business.industry ,Population ,Phases of clinical research ,medicine.disease ,Asymptomatic ,Gastroenterology ,Surgery ,Oncology ,Trastuzumab ,Internal medicine ,Heart failure ,medicine ,cardiovascular diseases ,medicine.symptom ,business ,education ,medicine.drug - Abstract
Background Patients (pts) with (w/) node-negative HER2−positive BCA have a higher risk of recurrence than those with node-negative HER2−negative disease. Several randomized trials have shown the benefit of chemotherapy (most with an anthracycline) and trastuzumab (H) for pts with node-positive and high-risk node-negative BCA. However, the benefit of chemotherapy and H needs to be further explored in the node-negative group. Due to the 2–4% risk of symptomatic congestive heart failure (CHF) with an anthracycline-based treatment (Rx) followed by H, we set out to conduct a study of a taxane-based Rx with H in a node-negative population. Design: This is a single arm, multicenter, phase II study of paclitaxel (T) (80 mg/m2) and trastuzumab (H) x 12 weekly (w) (4 mg/kg load →2 mg/kg) → H x 52 w (2 mg/kg weekly or 6 mg/kg q 3 w). Pts with HER2−positive BCA (IHC 3 + or FISH amplified at ≥ 2.0) with negative nodes (micrometastasis later allowed) and with a tumor size ≤ 3 cm were enrolled. The primary endpoint is disease-free survival. Secondary endpoints include the incidence of G 3/4 left ventricular systolic dysfunction or congestive heart failure (CHF). Pts had serial left ventricular ejection fraction (LVEF) monitored at baseline (BSLN), and at month (mo) 3, mo 6, and mo 12 w/a multigated acquisition scan or echocardiogram. H was held for significant asymptomatic (Asx) LVEF ↓ (10-15% ↓ from BSLN and < lower limit of normal or ≥ 16% ↓ from BSLN), and H was stopped for CHF. Results: From 10-9-2007 to 9-3-2010, 406 pts were enrolled. The median (med) age was 55 years (range 23–84 years); 118/406 (29%) had hypertension and 30/406 (7%) had diabetes. As of 6-1-2011, 307 are reported as off Rx of which 261 have completed protocol therapy; 99 remain on therapy. To date, 100%, 94%, 84%, and 83% of pts had LVEF monitoring at BSLN, mo 3, mo 6, and mo 12. The med LVEF at BSLN was 65% (range 50%-81%), at mo 3 was 64% (range 45%-81%), at mo 6 was 64% (range 45%-81%), and at mo 12 was 65% (range 37%-90%). Two pts had CHF; 1 pt had CHF at mo 11 (LVEF was 55% at BSLN and 37% w/CHF event) and 1 pt had CHF at mo 6 (LVEF was 66% at BSLN and 49% w/CHF event). To date, 13 pts had H held for significant Asx LVEF ↓; details on those who had appropriate LVEF recovery and had H restarted will be provided. All patients will have completed 12 mo of Rx by October 2011, and an accurate report of the incidence of CHF will be available. Conclusion: This represents the cardiac report of pts receiving TH as adjuvant Rx for node-negative (micrometastasis allowed) HER2 positive BCA. Both the CHF events and number of pts w/H hold due to significant Asx ↓ LVEF appear low. Overall, the serial med LVEFs remain stable throughout the 12 mo of Rx. Final data on all 406 pts will be available in December 2011. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-02.
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- 2011
41. P3-14-04: Assessment of Genomic Prognostic Signatures as Predictors of Response to Neoadjuvant Chemotherapy in Patients with Early Stage Breast Cancer
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Eva Culakova, William T. Barry, Geoffrey S. Ginsburg, Poniewierski, Neal Ready, Gary H. Lyman, M Huang, Nicole M. Kuderer, Paul K. Marcom, and Amy P. Abernethy
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Cancer ,Genomic signature ,Odds ratio ,medicine.disease ,Bioinformatics ,Minimal residual disease ,Breast cancer ,MammaPrint ,Internal medicine ,Diagnostic odds ratio ,Medicine ,business ,Oncotype DX - Abstract
Background: Based on results from randomized clinical trials, adjuvant and neoadjuvant chemotherapy (NCT) strategies in early stage breast cancer patients (ESBC) achieve comparable long term results. Recently, a number of genomic signatures have been reported, distinguishing patients with low versus high risk of recurrence. While developed primarily as prognostic assays, these classifiers have also been proposed to be predictive of benefit from systemic chemotherapy. Neoadjuvant studies provide an opportunity to evaluate their predictive value for response to NCT. Methods: A systematic review of gene expression profile studies in ESBC patients receiving chemotherapy was conducted. Medline search of original research articles of human studies published between January 2000 and February 2011 was based on key words and MeSH heading terms. Publications presenting outcomes for chemotherapy treated patients in groups stratified by multi-gene array signatures and utilizing a new independent cohort of patients compared to the original development cohort were selected. Information from eligible studies was extracted by dual abstraction. Reported results were synthesized into combined diagnostic odds ratio (DOR) using method of Mantel-Haenszel. This analysis is restricted to neoadjuvant studies investigating the association of genomic signature prognostic categories with objective tumor response to chemotherapy. Results: A total of 42 articles were eligible for data abstraction. Out of these, 6 publications evaluated response to NCT in good (low risk of recurrence) versus poor prognosis groups based on genomic prediction. Since two of the studies analyzed the same signature on a cohort with large overlap, only 5 studies were included in the final analysis, accounting for n=918 patients. Response consisted of pathologic complete response (pCR) in 3 studies, pCR or minimal residual disease (1 study), and clinical complete response (1 study). Prognostic genomic assays included Oncotype DX (1), MammaPrint (1), Genomic Grade Index (2) and PAM50 Risk of Relapse Score (1). Eight different chemotherapy regimens were utilized. The most common drugs were cyclophosphamide, anthracyclines, taxanes, and 5-fluorouracil. Across all genomic signatures, good prognosis patients, as defined by gene expression data, demonstrated consistently low rates of response to chemotherapy (median 3%, range 0–12%) compared to patients with less favorable prognosis (median 32%, range 19–43%). Odds ratio for response in poor versus good prognosis patients ranged from 3.9 to 21.7 with combined DOR= 6.6 (95% CI 3.9−11.3, P Conclusions: Across all genomic prognostic signatures reported, only a very small proportion of patients with signature predicted good prognosis achieved complete response to NCT. This suggests low sensitivity to chemotherapy among good prognosis patients, as determined by the prognostic genomic signatures. This further confirms the association between poor prognosis tumors and higher responsiveness to chemotherapy. Funding: NCI: UC2CA14041-01 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-04.
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- 2011
42. P5-13-17: Multigene Signature Assays in Patients with Early-Stage Breast Cancer (ESBC) Receiving Neoadjuvant Chemotherapy: An NCI-Funded Systematic Review and Evidence Summary of Predictive Performance
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Paul K. Marcom, Amy P. Abernethy, Eva Culakova, Poniewierski, Geoffrey S. Ginsburg, William T. Barry, M Huang, Gary H. Lyman, N. M. Kuderer, and Neal Ready
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,In patient ,Stage (cooking) ,business - Abstract
Background: A comprehensive literature search and evidence synthesis of multigene signatures predictive of response to systemic chemotherapy in patients with breast cancer was initiated as a part of an NCI-funded program on Comparative Effectiveness Research. Methods: Validation studies were sought of multigene signatures for prediction of chemotherapy response (favorable vs unfavorable) in ESBC patient cohorts different from those used for signature development. Pooled estimates [±95% CI] of assay performance for predicting clinical outcome included sensitivity, specificity, likelihood ratio, predictive value (PV) and predictive odds ratio (POR) utilizing mixed effects models based on the method of Mantel-Haenszel. Exploratory metaregression analyses on log (POR) were also performed. Studies were classified by validation type including cell lines to patients, independent internal sample, random split sample, or external validation. Evidence for publication bias was assessed by Egger's regression intercept and Begg and Mazumdar's rank correction. Results: Dual-blind review of abstracts identified 33 studies of neoadjuvant chemotherapy response of which 29 stratified treatment response by signature classifier category. Classifier development was based on tumor response prediction in 20 studies, prognosis in 5, and molecular classification in 4. The Table shows assay performance measures overall and by study validation type. Assay performance based on the POR was positively associated with overall study quality (P=.015) and journal impact factor (P=.020). However, strong evidence for publication bias was observed based on both regression intercept (P Conclusions: While assay performance in predicting response to neoadjuvant chemotherapy based on multigene classifiers is encouraging, a compelling need exists for greater methodologic rigor and standardization of reporting. The predictive performance of multigene assay signatures varies with the type of validation sample utilized with external validation providing the most conservative estimates. No differences were seen for assays developed for prediction, prognosis or molecular classification. Considerable evidence for publication bias exists reflecting a paucity of smaller negative studies. The clinical validity of genomic response prediction assays should be evaluated in patient cohorts independent of those utilized for signature development. The clinical utility of these assays must then be further assessed in comparative effectiveness studies compared to commonly utilized clinical and laboratory measures. Funding: NCI: UC2CA14041-01 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-17.
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- 2011
43. P1-13-03: Zoledronic Acid Induces an Immune Response in Breast Cancer Patients through Stimulation of Central Memory and Effector Memory gamma/delta T-Cells
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Erika Hamilton, Michael A. Morse, G Rocha, Herbert Kim Lyerly, Amy Hobeika, Kouros Owzar, Gretchen Kimmick, Jeffrey Peppercorn, K. L. Blackwell, and Paul K. Marcom
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Cancer Research ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Population ,Immune dysregulation ,medicine.disease_cause ,medicine.disease ,Peripheral blood mononuclear cell ,Metastatic breast cancer ,Immune system ,Cytokine ,Zoledronic acid ,Breast cancer ,Oncology ,Immunology ,Medicine ,business ,education ,medicine.drug - Abstract
Background Zoledronic acid (ZA) in combination with endocrine therapy (ET) and ovarian ablation (OA) reported a DFS advantage in premenopausal women with early stage breast cancer (EBC) in ABCSG-12. Emerging evidence from pre-clinical studies suggests that ZA increases gamma/delta T-cells (GDT), an immune cell population with anti-tumor activity. This study examined immune responses to a single dose of ZA in patients with either EBC or metastatic breast cancer (MBC) through sequential measurement of T-cells and immune regulatory cytokines. Methods Women with EBC/MBC, both pre- and post-menopausal, and no history of immune dysregulation who were scheduled to receive their first-ever dose of ZA were eligible. Blood was collected for serum and blood mononuclear cells at Day 0 (pre-ZA), Day 1 (18-48 hours post-ZA), Day 7 (Day 5–8 post ZA), and Day 28 (Day 25–32 post-ZA). GDT populations and cytokine responses were assayed using flow cytometry and multi-analyte profiling beads (Luminex), respectively. Relative changes from baseline at days 1, 7 and 18 were quantified using log-ratios and analyzed using the Wilcoxon signed-rank test. Results 24 patients were enrolled from Oct 2009 to Mar 2011. 75% of pts had MBC, and 25% had EBC, while 75% received ET, 17% received chemo (C), and 8% received other. Following ZA administration, a transient decrease in total GDT (CD3+/Vdelta2+) at Day 1 was seen (p Conclusion: ZA appears to induce a highly significant change in immune effector cells in both EBC and MBC patients receiving ET or C. Mobilization of anti-tumor T-cells with a decrease in total (non-specific) GDT followed by a marked increase post-ZA in specific central and effector memory GDT was seen at day 7. Significant increases in cytokine levels, like those seen in this study including those associated with Th1 responses or cell-mediated immunity, as well as IL-12 levels, have been implicated in direct anti-tumor activity. This apparent cytokine and cellular response to ZA could offer an important biologic mechanism for the anti-cancer activity reported in ABCSG-12. Further studies should be performed to determine which subsets of BC patients might achieve these described immune benefits from ZA. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-03.
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- 2011
44. Abstract PD06-09: Sentinel Node Biopsy Versus Axillary Lymph Node Dissection in Early-Stage Breast Cancer: A Meta-Analysis of Randomized Controlled Trials
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Nicole M. Kuderer, Gary H. Lyman, Paul K. Marcom, and Ja. Olson
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Absolute risk reduction ,Axillary Lymph Node Dissection ,Sentinel node ,medicine.disease ,law.invention ,Surgery ,Breast cancer ,Randomized controlled trial ,law ,Relative risk ,Internal medicine ,Meta-analysis ,Medicine ,Stage (cooking) ,business - Abstract
Background: Lymphatic mapping with sentinel node biopsy (SNB) has become a widely used technology for reducing morbidity associated with breast cancer staging despite limited data from randomized controlled trials (RCTs). A previous review of cohort studies conducted for ASCO guidelines prior to results from RCTs found considerable variation in SNB staging accuracy. (Kim et al, Cancer 2005; Lyman GH et al J Clin Oncol 2005). Early results from several RCTs of SNB have now been reported. Methods: A systematic review of RCTs of SNB for breast cancer staging was conducted utilizing electronic databases. Study eligibility was limited to RCTs comparing SNB alone in SNB negative patients versus axillary lymph node dissection (ALND) with or without prior SNB. SNB staging accuracy was assessed in study arms where patients were randomized to immediate ALND. Data abstraction was conducted by two independent reviewers. Rates of axillary, locoregional and all recurrence were evaluated along with all-cause and breast cancer-specific mortality. Heterogeneity was assessed by Cochran's Q-statistic and the Inconsistency Index (I2). Weighted summary measures of relative risk (RR) and absolute risk difference (ARD) with 95% CIs were estimated using the method of Mantel-Haenszel. Results: Seven eligible RCTs were identified of which six, involving 9,389 patients, reported either SNB performance and/or rates of recurrence and mortality. Eligibility in these studies was restricted to patients with clinically negative nodes with four limiting accrual to tumors Conclusions: The overall false negative rate with SNB greater than 10% and limited follow-up continue to raise concerns. While no increase in risk of recurrence or mortality in low risk patients managed primarily with SNB is evident to date, continued observation in these studies will be important in addition to more specific data on the accuracy and safety of SNB in higher risk patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-09.
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- 2010
45. Abstract PD3-01: Immune profile of small HER2+ tumors in the APT trial
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Kelly Marcom, Chau T. Dang, A. Getz, Ian E. Krop, Wafa Osmani, Deborah A. Dillon, Y.B. Tan, D. A. Yardley, William H. Barry, Kit Fuhrman, Beverly Moy, Sara M. Tolaney, Michele Baltay, EP Winer, and H Guo
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Cancer Research ,business.industry ,Tumor-infiltrating lymphocytes ,Phases of clinical research ,chemical and pharmacologic phenomena ,medicine.disease ,Variable Expression ,chemistry.chemical_compound ,Breast cancer ,Immune system ,Oncology ,Paclitaxel ,chemistry ,Trastuzumab ,Cancer research ,medicine ,Immunohistochemistry ,business ,medicine.drug - Abstract
Background: APT is a single arm multicenter, phase II study of paclitaxel and trastuzumab. Patients with HER2+ breast cancer with negative nodes and tumor size < 3 cm were eligible. Disease-free survival at 7 years was 93.3% with only 4 distant recurrences. Characterizing intrinsic subtype and immune profiles of these smaller tumors may help us better understand if the biology of smaller HER2+ tumors is different than larger tumors that have been previously characterized. Methods: Intrinsic subtyping by PAM50 and immune signatures by PanCancer Immune Profiling Panel were performed on the nCounter Analysis system on archival tissue. Tissue was also tested by immunohistochemistry for PDL1 (tumoral and immune cells) and was assessed for tumor infiltrating lymphocytes (TILs) using guidelines from the International TILs Working Group. TILS were categorized as follows: low (≤10%), intermediate (10-60%), high (≥60%); PD-L1 was characterized as low (0-1%), intermediate (1-10%), and high (>10%). Results: PAM50 data were available for 209 of the 406 cases: 142 (68%) were HER2-Enriched (HER2E), 22 (11%) Luminal A, 25 (12%) Luminal B, and 20 (10%) Basal-like. Immune profile information was available for 162 cases, of which 138 also had intrinsic subtype data. 184 cases were evaluated for PD-L1, and 210 cases for TILs. There was a strong correlation between PD-L1 in the tumor and lymphoid compartments (McNemar's chi-squared, p= 6.5x10-12). High tumoral PD-L1 was seen with higher frequency in the HER2E subset, while high immune cell PD-L1 and high TILs were seen with higher frequency within both the HER2E and Basal-like subtypes (Table). Immune profile data demonstrates that the T-cell signature has the strongest association with TILs, and that luminal A tumors tend to have very similar immune profiles while there is more variable expression of immune cell types with the basal-like tumors. Further work is ongoing to complete PAM50 and intrinsic subtype profiling of remaining tumors, and additional relationships between immune profile and intrinsic subtype will be presented at the meeting. Conclusions: The majority of small HER2+ breast cancers are HER2E, and tumors of this intrinsic subtype have the highest prevalence of high expression of PDL1 and high TILs, suggesting that these tumors may be more immunogenic than the luminal A and B HER2+ tumors. Further work to explore immune profile data by intrinsic subtype is ongoing and may have implications for future trial design. HER2ELuminal ALuminal BBasal-LikePDL1 (tumoral) Low6712159Intermediate16124High8100PDL1 (immune cell) Low3712113Intermediate27154High26116TILs Low6415165Intermediate36308High7011 Citation Format: Tolaney SM, Barry W, Guo H, Dillon D, Tan YB, Fuhrman K, Osmani W, Getz A, Baltay M, Dang C, Yardley D, Moy B, Marcom K, Krop I, Winer E. Immune profile of small HER2+ tumors in the APT trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-01.
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- 2018
46. Abstract P2-04-19: Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients
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Force, J, primary, Abbott, S, additional, Broadwater, G, additional, Kimmick, G, additional, Westbrook, K, additional, Hwang, S, additional, Kauff, N, additional, Stashko, I, additional, Weinhold, K, additional, Nair, S, additional, Hyslop, T, additional, Blackwell, K, additional, Castellar, E, additional, and Marcom, PK, additional
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- 2017
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47. Abstract P4-22-02: Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer
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Diéras, V, primary, Han, HS, additional, Robson, ME, additional, Palácová, M, additional, Marcom, PK, additional, Jager, A, additional, Bondarenko, I, additional, Citrin, D, additional, Campone, M, additional, Telli, ML, additional, Domchek, SM, additional, Friedlander, M, additional, Kaufman, B, additional, Ratajczak, C, additional, Coates, A, additional, Bonnet, P, additional, Qin, Q, additional, Qian, J, additional, Giranda, VL, additional, Shepherd, SP, additional, Puhalla, S, additional, and Isakoff, SJ, additional
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- 2017
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48. Abstract S2-05: Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study
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Han, HS, primary, Diéras, V, additional, Robson, ME, additional, Palácová, M, additional, Marcom, PK, additional, Jager, A, additional, Bondarenko, I, additional, Citrin, D, additional, Campone, M, additional, Telli, ML, additional, Domchek, SM, additional, Friedlander, M, additional, Kaufman, B, additional, Ratajczak, C, additional, Coates, A, additional, Bonnet, P, additional, Qin, Q, additional, Qian, J, additional, Giranda, VL, additional, Shepherd, SP, additional, Isakoff, SJ, additional, and Puhalla, S, additional
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- 2017
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49. Abstract P1-01-01: Circulating tumor cell number and CTC-endocrine therapy index predict clinical outcomes in ER positive metastatic breast cancer patients: Results of the COMETI Phase 2 trial
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Pamela J. Goodwin, M Block, Karen L. Tedesco, AM DeMichele, Costanza Paoletti, RT McCormack, Meredith M. Regan, Martha E. Brown, Ian E. Krop, Elizabeth P. Darga, John W. Smith, Paul K. Marcom, Emily M. Cannell, Paul J. Baratta, Eitan Amir, MC Liu, Kimberly Aung, Daniel F. Hayes, and Lowell L. Hart
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Metastatic breast cancer ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,Circulating tumor cell ,Breast cancer ,Internal medicine ,medicine ,Progression-free survival ,business ,Prospective cohort study ,neoplasms - Abstract
Introduction: Only half of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients (pts) benefit from endocrine therapy (ET). Circulating tumor cells (CTC) are prognostic in pts with MBC using CellSearch® technology. The CTC-endocrine therapy index (CTC-ETI) provides semi-quantitative analyses of CTC-ER (estrogen receptor), BCL2, HER2, and Ki67 expression. We hypothesized that CTC-ETI high (elevated CTC number and/or low expression of ER and BCL2, and high expression of HER2 and Ki-67) might predict resistance to ET in a prospective, multi-institutional clinical trial: COMETI-P2-2012.0 (NCT01701050). Methods: 121 pts with ER+, HER2 negative (-), and progressive MBC after one or more lines of ET or within 12 months (mos) of completing adjuvant ET, who were initiating a new ET, were enrolled after informed consent. CTC and CTC-ETI were determined as previously reported (Paoletti C et al, CCR 2015) at baseline (BL), 1, 2, 3, and 12 mos, and/or at the time of progression. Imaging was performed every 3 mos. Association of CTC levels and CTC-ETI with patient outcomes (progression free survival (PFS); rapid progression (RP) defined as progression within 3 mos) was assessed using logrank and Fisher's exact tests. Trial design estimated 85 PFS and 51 RP events, providing >90% power (2-sided a=0.05); pts with unsuccessful BL CTC-ETI or ineligible were unevaluable. Only baseline (BL) data are reported in this abstract. Results: 32% of enrolled pts had progression within 12 mos of completing adjuvant ET, whereas 40%, 20%, and 8% had 1, 2, ≥3 lines of ET for MBC. CTC-ETI was successfully determined in 93% of pts (90% CI, 88% to 97%). CTC were ≥5 CTC/7.5 ml whole blood in 37/108 (34%) pts evaluable for clinical validity. Elevated CTC was associated with worse PFS (median (m) PFS: 3.3 vs. 5.9 mos; P Conclusions: In this multi-institutional, prospective study, CTC-ETI was accurately determined, confirming the previously established analytical validity of the assay, meeting the primary objective of the trial. Elevated CTC and CTC-ETI high compared to low were associated with poor outcomes to ET. CTC-ETI distribution resulted in a small number of patients assigned to the intermediate group, restricting our ability to associate this group with outcomes. These results suggest that CTC-biomarker phenotype and enumeration have clinical validity. CTC-ETI may identify ER+ HER2– MBC pts who are unlikely to benefit from ET and might be better treated with ET in combination with other therapies or proceed to chemotherapy. Further analyses including CTC-ETI at serial time points during ET are planned. Citation Format: Paoletti C, Regan MM, Liu MC, Marcom PK, Hart LL, Smith II JW, Tedesco KL, Amir E, Krop IE, DeMichele AM, Goodwin PJ, Block M, Aung K, Cannell EM, Darga EP, Baratta PJ, Brown ME, McCormack RT, Hayes DF. Circulating tumor cell number and CTC-endocrine therapy index predict clinical outcomes in ER positive metastatic breast cancer patients: Results of the COMETI Phase 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-01.
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- 2017
50. Abstract P4-14-16: T-cell clonality increases after neoadjuvant treatment with trastuzumab and pertuzumab
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Howie, LJ, primary, Marcom, PK, additional, Topping, DL, additional, Force, J, additional, Emerson, R, additional, Bhavsar, NA, additional, Abbott, SE, additional, Parks, M, additional, Robins, HS, additional, and Blackwell, KL, additional
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- 2016
- Full Text
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