235 results on '"Jo Chien"'
Search Results
2. GustoGear: A Cross-Modal Interface Emphasizing Tactile and Flavor Communication for Extended Reality.
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Po Yu Chen, Yi Chun Ko, and Jo Chien Wang
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- 2024
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3. Erratum: 53 The development of a multi-institutional prospective registry for patients with metastatic invasive lobular carcinoma: identifying new markers of disease progression - CORRIGENDUM.
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Rothschild, Harriet, Jo Chien, A, Jankowitz, Rachel, Magbanua, Mark, Mouabbi, Jason, Levine, Julia, Mukhtar, Rita, and Shatsky, Rebecca
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[This corrects the article DOI: 10.1017/cts.2023.142.].
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- 2023
4. Tamoxifen or aromatase inhibitors with ovarian function suppression in pre-menopausal stage I-III lobular breast cancer
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Helena Record, Elle Clelland, Harriet T. Rothschild, Mandeep Kaur, A. Jo Chien, Michelle Melisko, Hope S. Rugo, Firdows Mujir, Laura Huppert, and Rita A. Mukhtar
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract While adjuvant treatment with the selective-estrogen receptor modulator (SERM) tamoxifen has been the standard of care for pre-menopausal patients with hormone receptor (HR) positive breast cancer, recent trials showed a benefit of aromatase inhibitors (AI) and ovarian function suppression (OFS) for some patients. The approach to endocrine therapy has not been well studied in pre-menopausal patients with invasive lobular carcinoma (ILC). We identified 202 pre-menopausal patients with HR positive stage I-III ILC in an institutional database. We investigated factors associated with endocrine therapy type and determined changes in systemic therapy from 1990–2021. We evaluated associations between endocrine therapy type and disease-free survival (DFS) with a multivariate Cox proportional hazards model. Of 202 patients, most (69.3%) were prescribed a SERM (99.3% tamoxifen). Those who received an AI had significantly higher stage disease. Over time, use of OFS and AI increased significantly in stage II or III cases (from 0% in 1990 to 56% after 2015 for stage II; from 0% to 80% after 2015 for stage III). Concurrently, adjuvant chemotherapy use significantly decreased in stage II cases (from 67% to 19%). In an exploratory multivariable model, longer duration of AI compared to tamoxifen was associated with significantly improved DFS (HR 0.31; 95% CI 0.11–0.86; p = 0.025). While most pre-menopausal patients received adjuvant tamoxifen, the use of OFS and AIs increased significantly over time. The association between AI use and improved DFS may be consistent with prior randomized trials and warrants further investigation into predictive factors to guide treatment selection.
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- 2023
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5. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.
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Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, and Esserman, Laura J
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Diabetes ,Cancer ,Breast Cancer ,6.1 Pharmaceuticals - Abstract
I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.
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- 2021
6. Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer
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Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, A. Jo Chien, Hope S. Rugo, Adam Brufsky, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A. García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A. Cheong, Benjamin Schnappauf, Dieter Semsek, Christian F. Singer, Navid Foruzan, Daniel DiPrimeo, Leanne McCulloch, Sara A. Hurvitz, and Carlos H. Barcenas
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Neratinib ,Tyrosine kinase inhibitor ,HER2-positive ,Breast cancer ,Early stage ,Diarrhea prophylaxis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. Methods: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. Results: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. Conclusions: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. ClinicalTrials.gov registration number: NCT02400476.
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- 2023
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7. Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer
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Julie E. Lang, Andres Forero-Torres, Douglas Yee, Christina Yau, Denise Wolf, John Park, Barbara A. Parker, A. Jo Chien, Anne M. Wallace, Rashmi Murthy, Kathy S. Albain, Erin D. Ellis, Heather Beckwith, Barbara B. Haley, Anthony D. Elias, Judy C. Boughey, Rachel L. Yung, Claudine Isaacs, Amy S. Clark, Hyo S. Han, Rita Nanda, Qamar J. Khan, Kristen K. Edmiston, Erica Stringer-Reasor, Elissa Price, Bonnie Joe, Minetta C. Liu, Lamorna Brown-Swigart, Emanuel F. Petricoin, Julia D. Wulfkuhle, Meredith Buxton, Julia L. Clennell, Ashish Sanil, Scott Berry, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Adam L. Asare, Jeffrey B. Matthews, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, W. Fraser Symmans, Laura J. van ‘t Veer, Nola M. Hylton, Angela M. DeMichele, Donald A. Berry, and Laura J. Esserman
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51–52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer. Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379
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- 2022
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8. GustoGear: A Cross-Modal Interface Emphasizing Tactile and Flavor Communication for Extended Reality
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Chen, Po Yu, primary, Ko, Yi Chun, additional, and Wang, Jo Chien, additional
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- 2024
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9. 53 The development of a multi-institutional prospective registry for patients with metastatic invasive lobular carcinoma: identifying new markers of disease progression – CORRIGENDUM
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Harriet T Rothschild, A Jo Chien, Rachel C Jankowitz, Mark JM Magbanua, Jason A Mouabbi, Rebecca A Shatsky, Julia Levine, and Rita A Mukhtar
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Medicine - Published
- 2023
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10. The incidence of discordant clinical and genomic risk in patients with invasive lobular or ductal carcinoma of the breast: a National Cancer Database Study
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Mary Kathryn Abel, Amy M. Shui, Michelle Melisko, A. Jo Chien, Emi J. Yoshida, Elizabeth M. Lancaster, Laura Van ‘T Veer, Laura J. Esserman, and Rita A. Mukhtar
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract When molecular testing classifies breast tumors as low risk but clinical risk is high, the optimal management strategy is unknown. One group of patients who may be more likely to have such discordant risk are those with invasive lobular carcinoma of the breast. We sought to examine whether patients with invasive lobular carcinoma are more likely to have clinical high/genomic low-risk tumors compared to those with invasive ductal carcinoma, and to evaluate the impact on receipt of chemotherapy and overall survival. We conducted a cohort study using the National Cancer Database from 2010–2016. Patients with hormone receptor positive, HER2 negative, stage I-III breast cancer who underwent 70-gene signature testing were included. We evaluated the proportion of patients with discordant clinical and genomic risk by histology using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models with and without propensity score matching. A total of 7399 patients (1497 with invasive lobular carcinoma [20.2%]) were identified. Patients with invasive lobular carcinoma were significantly more likely to fall into a discordant risk category compared to those with invasive ductal carcinoma (46.8% versus 37.1%, p
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- 2021
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11. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
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Amy S. Clark, Christina Yau, Denise M. Wolf, Emanuel F. Petricoin, Laura J. van ‘t Veer, Douglas Yee, Stacy L. Moulder, Anne M. Wallace, A. Jo Chien, Claudine Isaacs, Judy C. Boughey, Kathy S. Albain, Kathleen Kemmer, Barbara B. Haley, Hyo S. Han, Andres Forero-Torres, Anthony Elias, Julie E. Lang, Erin D. Ellis, Rachel Yung, Debu Tripathy, Rita Nanda, Julia D. Wulfkuhle, Lamorna Brown-Swigart, Rosa I. Gallagher, Teresa Helsten, Erin Roesch, Cheryl A. Ewing, Michael Alvarado, Erin P. Crane, Meredith Buxton, Julia L. Clennell, Melissa Paoloni, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Katherine Steeg, Adam Asare, Jeffrey B. Matthews, Scott Berry, Ashish Sanil, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, Richard B. Schwab, W. Fraser Symmans, Nola M. Hylton, Donald A. Berry, Laura J. Esserman, and Angela M. DeMichele
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Science - Abstract
HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.
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- 2021
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12. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer
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Douglas Yee, Claudine Isaacs, Denise M. Wolf, Christina Yau, Paul Haluska, Karthik V. Giridhar, Andres Forero-Torres, A. Jo Chien, Anne M. Wallace, Lajos Pusztai, Kathy S. Albain, Erin D. Ellis, Heather Beckwith, Barbara B. Haley, Anthony D. Elias, Judy C. Boughey, Kathleen Kemmer, Rachel L. Yung, Paula R. Pohlmann, Debu Tripathy, Amy S. Clark, Hyo S. Han, Rita Nanda, Qamar J. Khan, Kristen K. Edmiston, Emanuel F. Petricoin, Erica Stringer-Reasor, Carla I. Falkson, Melanie Majure, Rita A. Mukhtar, Teresa L. Helsten, Stacy L. Moulder, Patricia A. Robinson, Julia D. Wulfkuhle, Lamorna Brown-Swigart, Meredith Buxton, Julia L. Clennell, Melissa Paoloni, Ashish Sanil, Scott Berry, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Adam L. Asare, Jeffrey B. Matthews, Nola M. Hylton, Angela DeMichele, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, W. Fraser Symmans, Laura J. van‘t Veer, Donald A. Berry, and Laura J. Esserman
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.
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- 2021
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13. Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk
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Mark Jesus M. Magbanua, Wen Li, Denise M. Wolf, Christina Yau, Gillian L. Hirst, Lamorna Brown Swigart, David C. Newitt, Jessica Gibbs, Amy L. Delson, Ekaterina Kalashnikova, Alexey Aleshin, Bernhard Zimmermann, A. Jo Chien, Debu Tripathy, Laura Esserman, Nola Hylton, and Laura van ‘t Veer
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p
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- 2021
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14. Decreased enrollment in breast cancer trials by histologic subtype: does invasive lobular carcinoma resist RECIST?
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Mary Kathryn Abel, Michelle E. Melisko, Hope S. Rugo, A. Jo Chien, Italia Diaz, Julia K. Levine, Ann Griffin, Joseph McGuire, Laura J. Esserman, Hala T. Borno, and Rita A. Mukhtar
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Enrollment in metastatic breast cancer trials usually requires measurable lesions, but patients with invasive lobular carcinoma (ILC) tend to form diffuse disease. We found that the proportion of patients with metastatic ILC enrolled in clinical trials at our institution was significantly lower than that of patients with invasive ductal carcinoma (IDC). Possible links between requiring measurable disease and decreased enrollment of ILC patients require further study to ensure equitable trial access.
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- 2021
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15. Evaluation of the Pathways for Survivors Program to Address Breast Cancer Survivorship–Associated Distress: Survey Study
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Saumya Umashankar, Matina Elise Mamounas, Madeline Matthys, Edward Kenji Hadeler, Emily Claire Wong, Greg Hicks, Jimmy Hwang, Amy Jo Chien, Hope S Rugo, Deborah Hamolsky, Laura Esserman, and Michelle Melisko
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundPatients with breast cancer frequently experience escalation of anxiety after completing curative treatment. ObjectiveThis study evaluated the acceptability and psychological impact of a 1-day workshop to emphasize behavioral strategies involving intention and self-efficacy. MethodsBreast cancer survivors who attended a 1-day Pathways for Survivors workshop provided feedback and completed electronic quality of life (QOL) questionnaires at baseline, 1 and 6 weeks, and 6 months after the workshop. Attendees’ baseline QOL scores were compared to follow-up (FUP) scores. Scores from patients receiving routine FUP care were also compiled as a reference population. ResultsIn total, 77 patients attended 1 of 9 workshops. The mean satisfaction score was 9.7 out of 10 for the workshop and 9.96 out of 10 for the moderator. Participants’ baseline mean Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scores were 57.8 (SD 6.9) and 55.3 (SD 7.5), respectively, which were significantly higher than those of patients receiving routine FUP care (49.1, SD 8.3 and 47.3 SD 8.0, respectively). PROMIS anxiety and depression scores decreased, and the Happiness Index Profile (HIP-10) score—measuring intention and resiliency—increased significantly at 1- and 6-week FUPs. ConclusionsThe Pathways for Survivors program was favorably received. Anxiety and depression decreased significantly at 1- and 6-weeks after the workshop and remained below baseline at 6 months. Increased HIP-10 scores suggest that patients acquired and implemented skills from the workshop. A 1-day workshop led by a lay moderator significantly improved several psychological measures, suggesting that it may be a useful and time-efficient strategy to improve QOL in breast cancer survivors. We are investigating whether an abbreviated “booster” of the intervention at a later date could further improve and maintain QOL gains.
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- 2022
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16. HER-2 low status in early-stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series
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Harriet T. Rothschild, Elle Clelland, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, W. Fraser Symmans, Christopher J. Schwartz, A. Jo Chien, and Rita A. Mukhtar
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Cancer Research ,Carcinoma ,Early-stage ,Clinical Sciences ,Oncology and Carcinogenesis ,Breast Neoplasms ,Prognosis ,Invasive lobular carcinoma ,Disease-Free Survival ,Lobular ,ErbB-2 ,Oncology ,Ductal ,Breast Cancer ,Humans ,Female ,Breast ,HER2-low ,Oncology & Carcinogenesis ,Receptor ,Cancer - Abstract
Purpose HER2 overexpression has a central role in breast cancer carcinogenesis and is associated with poor prognosis if untreated. Lately, identification of HER2-low breast cancer has been proposed to select patients for novel HER2-directed chemotherapy and includes cancers with immunohistochemistry 1 + or 2 + with negative FISH, encompassing approximately 55–60% of all breast carcinomas. In early-stage breast cancer, the prognostic significance of HER2 low-disease is less well understood, with a particular paucity of data evaluating the prevalence and implications of HER2-low status in invasive lobular carcinoma (ILC). Methods We evaluated 666 stage I-III ILC tumors from a prospectively maintained institutional database, comparing clinicopathologic features and disease-free survival (DFS) using a multivariable Cox proportional hazards model. Results HER2-low status was common in this cohort of patients with ILC, but most clinicopathologic features did not differ between HER2-low and HER2-negative cases. However, when adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse disease-free survival (DFS) than those with HER2-negative tumors (hazard ratio 2.0, 95% confidence interval 1.0–4.1, p = 0.05). Conclusion This difference in DFS supports the notion that HER2-low and HER2-negative early stage ILC may differ clinically, despite similar clinicopathologic features. Further investigation into the potential benefit of HER2 targeted therapy in HER2-low early-stage breast cancer, and specifically lobular cancer, is warranted to ensure optimal outcomes in this distinct tumor subtype.
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- 2023
17. Abstract P3-09-01: Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP)
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Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, and Jo Chien
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Cancer Research ,Oncology - Abstract
Background: Treatment of estrogen receptor (ER)-positive breast cancer with selective estrogen receptor degraders (SERDs) frequently results in the loss or reduction of ER expression. Whether these changes are due to on-target effects of SERDs degrading ER or arise as a mechanism of tumor resistance with associated changes in cellular phenotypes remains unknown. It is critical to distinguish between these possibilities to accurately assess treatment response and determine the most appropriate subsequent therapy. To this end, we created and conducted molecular analyses on patient-derived organoid cultures from post-treatment tissue in patients receiving neoadjuvant SERD therapy for early-stage ER+ breast cancer in the I-SPY2 Endocrine Optimization Protocol (EOP). Methods: The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2-negative breast cancer. Enrollment is ongoing, with patients receiving amcenestrant neoadjuvantly for 6 months until the day before surgery. Tumor tissue is collected at baseline, 3 weeks, and at surgery. Organoids were generated from post-treatment surgical samples. Organoid cultures were optimized based on established methods (Dekkers et al., Nature Protocols, 2021) to assess ER levels and activity. Pre- and post-treatment tissue samples were also assessed for ER, PR, Ki67, and GATA3, a luminal marker and transcription factor that is functionally linked with ER, via immunohistochemistry. Results: In 7 patients with both pre- and post-treatment tissue samples including fresh surgical samples for organoid generation, the ER in baseline tumor tissue was >=90% in all patients, PR ranged from 40-90%, and Ki67 ranged from 5-30%. In post-treatment surgical tissue from these cases, ER ranged from 0-30%, PR from 0-50%, Ki67 from < 1%-10%, and GATA3 was positive in 5 of 5 cases tested to-date. The creation of organoids from residual disease at surgery was attempted for these 7 patients, with organoids successfully propagated in 5 cases thus far. 3 of 5 organoid cultures were ready for analysis and in all cases strong ER and PR expression in organoids was observed after culture for > 1 month in the absence of amcenestrant. Detailed gene expression profiling (including Mammaprint/Blueprint) and gene set enrichment analyses (GSEA) to assess for intrinsic breast cancer subtype and ER activity in each sample and corresponding organoid culture are in progress and will be reported with the full dataset. Conclusion: Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact. In general, patient-derived tumor organoid cultures modeling residual disease states can be a useful adjunct to existing methods used to monitor the effects of neoadjuvant endocrine therapy and is being explored in the I-SPY EOP trial. Citation Format: Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, Jo Chien. Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP) [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 P3-09-01.
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- 2023
18. Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study
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Mark Jesus M. Magbanua, Laura van ‘t Veer, Amy S. Clark, A. Jo Chien, Judy C. Boughey, Hyo S. Han, Anne Wallace, Heather Beckwith, Minetta C. Liu, Christina Yau, E. Paul Wileyto, Andrea Ordonez, Tulasi I. Solanki, Feng Hsiao, Jen Chieh Lee, Amrita Basu, Lamorna Brown Swigart, Jane Perlmutter, Amy L. Delson, Lauren Bayne, Shannon Deluca, Stephanie S. Yee, Erica L. Carpenter, Laura J. Esserman, John W. Park, Lewis A. Chodosh, and Angela DeMichele
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Cancer Research ,Oncology - Published
- 2023
19. Clinical characteristics and outcomes in patients with metastatic breast cancer and pseudocirrhosis: a single center retrospective cohort study
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Laura A. Huppert, Zak Walker, Moming Li, Mi-Ok Kim, Jennifer Callan, Danielle Brandman, Melanie Majure, Michelle E. Melisko, Hope S. Rugo, Spencer Behr, and A. Jo Chien
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Cancer Research ,Oncology - Abstract
Pseudocirrhosis is a term used to describe changes in hepatic contour that mimic cirrhosis radiographically, but lack the classic pathologic features of cirrhosis. This radiographic finding is frequently found in patients with metastatic breast cancer (MBC), but the risk factors and clinical consequences are poorly understood.In this retrospective study, we identified patients with MBC and pseudocirrhosis who were treated at a single center from 2002 to 2021. We used chart extraction and radiology review to determine demographic characteristics, treatment history, imaging features, and complications of pseudocirrhosis.120 patients with MBC and pseudocirrhosis were identified with the following BC subtypes: hormone receptor (HR) positive, HER2 negative (n = 99, 82.5%), HR+/HER2+ (n = 14, 11.7%), HR- /HER2+ (n = 3, 2.5%), and triple negative (TNBC; n = 4, 3.3%). All patients had liver metastases and 82.5% (n = 99) had 15 liver lesions. Thirty-six patients (30%) presented with de novo metastatic disease. Median time from MBC diagnosis to pseudocirrhosis was 29.2 months. 50% of patients had stable or responding disease at the time of pseudocirrhosis diagnosis. Sequelae of pseudocirrhosis included radiographic ascites (n = 97, 80.8%), gastric/esophageal varices (n = 68, 56.7%), splenomegaly (n = 26, 21.7%), GI bleeding (n = 12, 10.0%), and hepatic encephalopathy (n = 11, 9.2%). Median survival was 7.9 months after pseudocirrhosis diagnosis. Radiographic ascites was associated with shorter survival compared to no radiographic ascites (42.8 vs. 76.2 months, p = 0.001).This is the largest case series of patients with MBC and pseudocirrhosis. Nearly all patients had HR+ MBC and extensive liver metastases. Survival was short after pseudocirrhosis and prognosis worse with radiographic ascites.
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- 2022
20. ACR11 modulates levels of reactive oxygen species and salicylic acid-associated defense response in Arabidopsis
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Shashi Kant Singh, Tzu-Ying Sung, Tsui-Yun Chung, Shao-Yu Lin, Sang-Chu Lin, Jo-Chien Liao, Wei-Yu Hsieh, and Ming-Hsiun Hsieh
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Medicine ,Science - Abstract
Abstract The ACT domain (aspartate kinase, chorismate mutase and TyrA), an allosteric effector binding domain, is commonly found in amino acid metabolic enzymes. In addition to ACT domain-containing enzymes, plants have a novel family of ACT domain repeat (ACR) proteins, which do not contain any recognizable catalytic domain. Arabidopsis has 12 ACR proteins, whose functions are largely unknown. To study the functions of Arabidopsis ACR11, we have characterized two independent T-DNA insertion mutants, acr11-2 and acr11-3. RNA gel-blot analysis revealed that the expression of wild-type ACR11 transcripts was not detectable in the acr11 mutants. Interestingly, a lesion-mimic phenotype occurs in some rosette leaves of the acr11 mutants. In addition, high levels of reactive oxygen species (ROS), salicylic acid (SA), and callose accumulate in the mutant leaves when grown under normal conditions. The expression of several SA marker genes and the key SA biosynthetic gene ISOCHORISMATE SYNTHASE1 is up-regulated in the acr11 mutants. Furthermore, the acr11 mutants are more resistant to the infection of bacterial pathogen Pseudomonas syringae pathovar tomato DC3000. These results suggest that ACR11 may be directly or indirectly involved in the regulation of ROS and SA accumulation, which in turn modulates SA-associated defense responses and disease resistance in Arabidopsis.
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- 2018
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21. Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy
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Mark Jesus M. Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W. Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Wen Li, Amy L. Delson, Smita Asare, Minetta C. Liu, Kathy Albain, A. Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W. Fraser Symmans, Douglas Yee, Nola M. Hylton, Laura J. Esserman, Angela M. DeMichele, Hope S. Rugo, and Laura J. van ’t Veer
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Cancer Research ,Oncology - Published
- 2023
22. 53 The development of a multi-institutional prospective registry for patients with metastatic invasive lobular carcinoma: identifying new markers of disease progression
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Rothschild, Harriet, primary, Jankowitz, Rachel, additional, Shatsky, Rebecca, additional, Mouabbi, Jason, additional, Levine, Julia, additional, and Jo Chien, Alliance A, additional
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- 2023
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23. Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial
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Nancy U. Lin, Rashmi K. Murthy, Vandana Abramson, Carey Anders, Thomas Bachelot, Philippe L. Bedard, Virginia Borges, David Cameron, Lisa A. Carey, A. Jo Chien, Giuseppe Curigliano, Michael P. DiGiovanna, Karen Gelmon, Gabriel Hortobagyi, Sara A. Hurvitz, Ian Krop, Sherene Loi, Sibylle Loibl, Volkmar Mueller, Mafalda Oliveira, Elisavet Paplomata, Mark Pegram, Dennis Slamon, Amelia Zelnak, Jorge Ramos, Wentao Feng, Eric Winer, Institut Català de la Salut, [Lin NU] Dana-Farber Cancer Institute, Boston, Massachusetts. [Murthy RK] MD Anderson Cancer Center, Houston, Texas. [Abramson V] Vanderbilt University Medical Center, Nashville, Tennessee. [Anders C] Duke Cancer Institute, Durham, North Carolina. [Bachelot T] Centre Léon Bérard, Lyon, France. [Bedard PL] University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. [Oliveira M] Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,neoplasias::neoplasias por localización::neoplasias del sistema nervioso::neoplasias del sistema nervioso central::neoplasias cerebrales [ENFERMEDADES] ,Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores] ,Quimioteràpia combinada ,Medicaments antineoplàstics - Efectes secundaris ,Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms::Brain Neoplasms [DISEASES] ,Oncology ,Metàstasi ,Cervell - Càncer - Tractament ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Mama - Càncer - Tractament ,Other subheadings::Other subheadings::/adverse effects [Other subheadings] - Abstract
ImportanceIt is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs.ObjectiveTo describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up.Design, Setting, and ParticipantsHER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed.InterventionsPatients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle).Main Outcomes and MeasuresEvaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion–free survival in all patients. Only OS was prespecified before the primary database lock.ResultsAt baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]).Conclusions and RelevanceThis subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.Trial RegistrationClinicalTrials.gov Identifier: NCT02614794
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- 2023
24. Abstract P5-18-02: Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer
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Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, and Carlos H Barcenas
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Cancer Research ,Oncology - Abstract
Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy and in combination with capecitabine for HER2+ metastatic breast cancer. Diarrhea is the most frequently reported on-target side effect associated with neratinib; in the ExteNET adjuvant trial, where no mandatory anti-diarrheal prophylaxis was used, 39.8% of patients reported grade 3 diarrhea and 16.8% of patients discontinued neratinib due to diarrhea. The CONTROL trial (Clinicaltrials.gov: NCT02400476) was designed to investigate pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or neratinib dose escalation (DE) for the prevention of neratinib-associated diarrhea. Data for the loperamide, budesonide and colestipol cohorts have been reported previously [Barcenas et al. Ann Oncol 2020]. The final findings for the two DE regimen cohorts are reported here. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer received oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) neratinib DE + loperamide PRN (two cohorts). DE1 schedule: neratinib 120 mg/day for week 1, 160 mg/day for week 2, then 240 mg/day from week 3 onwards to complete 12 months of treatment. DE2 schedule: neratinib 160 mg/day for weeks 1&2, 200 mg/day for weeks 3&4, then 240 mg/day from week 5 onwards up to 12 months. Both DE cohorts included loperamide PRN. Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Results: A total of 563 patients were enrolled in CONTROL. All preventive strategies reduced the incidence of grade 3 diarrhea compared with that seen in ExteNET (historical control: 39.8%). Median cumulative duration of grade 3 diarrhea ranged from 2-3.5 days across the CONTROL study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET). The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for loperamide alone. Adoption of neratinib DE, particularly the 2-week DE schedule (DE1), most markedly reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET (see Table). Conclusions: Neratinib DE + loperamide PRN during the first 2 weeks of treatment (DE1 cohort) was associated with the lowest rates of grade 3 diarrhea (13.3%) and diarrhea-related discontinuations (3.3%) compared with all other anti-diarrheal strategies investigated in CONTROL. These final findings from the study show improved tolerability of neratinib with all diarrhea prophylaxis strategies and suggest that neratinib DE1 with loperamide PRN allows patients to stay on treatment longer and receive the full benefit of neratinib therapy. Table. Patient disposition and diarrhea characteristics: ExteNET vs CONTROL DE cohortsExteNET(n=1408)CONTROL DE1 (n=60)CONTROL DE2 (n=62)Patients completing 1 year of neratinib treatment, %617874Median duration of treatment, months (range)11.6 (2.5–11.9)12.0 (0.2–12.4)11.9 (0.3–14.5)Diarrhea, %Grade 339.813.327.4Grade 4 Citation Format: Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, Carlos H Barcenas. Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-02.
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- 2022
25. Abstract OT1-10-02: I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer
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A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, and Laura J Esserman
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Cancer Research ,Oncology - Abstract
Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-10-02.
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- 2022
26. Abstract PD10-07: Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies
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Hatem Soliman, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Beverly Parker, Laura Sit, Smita Asare, Doug Yee, Angie DeMichele, Rita Nanda, Lajos Pusztai, Don Berry, Laura Esserman, and Laura Van't Veer
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Cancer Research ,Oncology - Abstract
Background: The CK12 expression signature consists of genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13 and was previously shown to associate with the presence of T and B cell rich tertiary lymphoid structures in melanoma and other cancers, and with better patient survival independent of tumor staging and treatment. I-SPY 2 is a biomarker-rich, phase II neoadjuvant platform trial for high risk early stage breast cancer. Here we leverage the I-SPY 2 biomarker program to test the hypothesis that this signature associates with sensitivity to neoadjuvant immunotherapies and potentially other classes cancer therapeutics in breast cancer. Methods: Data from 1130 patients across 12 arms of I-SPY2 (control (ctr): 210; veliparib/carboplatin (VC): 71; neratinib (N): 114; MK2206: 93; ganitumab: 106; ganetespib: 93; AMG386: 134; TDM1/pertuzumab(P): 52; H/P: 44; pembrolizumab (pembro): 69; durvalumab/olaparib (durva/olap): 71; pembro/SD101: 72) were available for analysis. Pre-treatment FF (n=987) or FFPE (n=143) biopsies were assayed using Agilent gene expression arrays. Signature scores were calculated as the average expression level across the 12 genes, after z-score normalization. We used logistic modeling to assess association with pCR in each arm in a model adjusting for HR and HER2 (likelihood ratio test, p Citation Format: Hatem Soliman, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Beverly Parker, Laura Sit, Smita Asare, Doug Yee, Angie DeMichele, Rita Nanda, Lajos Pusztai, Don Berry, Laura Esserman, Laura Van't Veer. Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-07.
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- 2022
27. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
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Denise M. Wolf, Jane Perlmutter, Judy C. Boughey, A. Jo Chien, Meredith Buxton, Gillian L. Hirst, Douglas Yee, Angela DeMichele, Andres Forero-Torres, Scott M. Berry, Erin D. Ellis, Anthony D. Elias, Julia Wulfkuhle, Michael Alvarado, Christina Yau, Stacy L. Moulder, Nola M. Hylton, Rita Nanda, Amy Wilson, Adam Asare, Debu Tripathy, Claudine Isaacs, Melissa Paoloni, Rosa I. Gallagher, Laura J. Esserman, Richard Schwab, W. Fraser Symmans, Cheryl Ewing, Laura J. van't Veer, Jeffrey B. Matthews, Teresa Helsten, Julia L. Clennell, Barbara Haley, Emanuel F. Petricoin, Katherine Steeg, Smita Asare, Ashish Sanil, Rachel L. Yung, Erin P. Crane, Erin Roesch, Hyo S. Han, Ruby Singhrao, Michelle E. Melisko, Hope S. Rugo, Kathy S. Albain, Donald A. Berry, Anne M. Wallace, Julie E. Lang, Amy S. Clark, Kathleen Kemmer, and Lamorna Brown-Swigart
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Oncology ,Receptor, ErbB-2 ,General Physics and Astronomy ,Ado-Trastuzumab Emtansine ,chemistry.chemical_compound ,Breast cancer ,ErbB-2 ,Trastuzumab ,Monoclonal ,skin and connective tissue diseases ,Humanized ,Cancer ,Multidisciplinary ,Tumor ,medicine.diagnostic_test ,Middle Aged ,Neoadjuvant Therapy ,Paclitaxel ,6.1 Pharmaceuticals ,Pertuzumab ,medicine.drug ,Receptor ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Science ,Clinical Trials and Supportive Activities ,Context (language use) ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,Article ,General Biochemistry, Genetics and Molecular Biology ,Antibodies ,Clinical Research ,Internal medicine ,Biopsy ,Breast Cancer ,Biomarkers, Tumor ,medicine ,Humans ,Doxorubicin ,Maytansine ,neoplasms ,Aged ,business.industry ,Evaluation of treatments and therapeutic interventions ,General Chemistry ,Translational research ,medicine.disease ,chemistry ,business ,Biomarkers - Abstract
HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.
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- 2021
28. Abstract P2-03-16: Quantifying estrogen and progesterone receptor status in early-stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series
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Elle Clelland, Harriet T. Rothschild, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, Mary Kathryn Abel, W. Fraser Symmans, Jo Chien, Christopher J. Schwartz, and Rita Mukhtar
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Cancer Research ,Oncology - Abstract
Background: Recent guidelines regarding estrogen (ER) and progesterone (PR) receptor testing from the American Society of Clinical Oncology and College of American Pathologists defined a new reporting category of ER-low positive breast cancer for tumors with 1-10% ER expression by immunohistochemistry (IHC). The clinical implications of ER-low positivity are incompletely understood, especially in invasive lobular carcinoma (ILC), the second most common type of breast cancer. Given the rarity of low-ER positivity in ILC, we evaluated tumor features and outcomes associated with a spectrum of ER/PR positivity in a monoinstitutional ILC cohort. Methods: We analyzed cases of stage I-III ILC with available IHC reports. Based on prior published categories in ILC, we classified ER as low, medium, or high as defined by ER staining of 10–69%, 70–89%, and ≥90% respectively. PR negative, low, and high tumors were defined by 0%, < 20%, or ≥20% staining respectively. We used chi-squared tests, t-tests, and Cox proportional hazards models in Stata 16.1 to evaluate associations between ER/PR categories including clinicopathologic variables and event-free survival (EFS). Results: Of 744 cases, 24 (3.2%) were ER negative and 10 (1.3%) were ER-low positive as defined by 1-10% positive staining. 713 remaining cases had ER positivity ≥ 10% and comprised the cohort categories of ER low, medium, and high for this study (11.2%, 15.0%, and 73.8% respectively). In 751 cases with PR data, 122 (16.2%) were PR negative, 145 (19.4%) were PR low and 483 (64.3%) were PR high. ER high status was significantly associated with older age (mean 56.7, 56.7, and 60.6 years in ER low, medium, and high respectively, p=0.0005). ER low was associated with PR negative and low status (42.3% were PR neg/low and ER low, versus 37.4% with ER medium and 29.9% in ER high, p=0.045), and more likely to have overexpression of HER2 (9.7%, 9.0%, and 2.9% ER low, medium, high, respectively, p=0.002). ER low tumors were more likely to be grade 1 than ER medium or high (41.8%, 29.8% and 24.5% respectively, p=0.025), and have positive surgical margins (39.4%, 35.9% and 23.9% respectively, p=0.002). ER status was not associated with Ki67, stage, body mass index (BMI), lymphovascular invasion, lobular carcinoma in situ (LCIS), pleomorphic histology, local therapy, or chemotherapy use. In contrast, PR high was significantly associated with younger age (57.6 versus 63.5 years in PR low, p< 0.0001). PR low was associated with HER2 overexpression (8.6% versus 3.2% in PR high, p=0.002). PR low cases were more likely to present at higher stages (15.8% stage III versus 10.1% stage III in PR high, p=0.032), to be pleomorphic (16.8% versus 8.2%, p< 0.001), and to receive chemotherapy (30.8% versus 23.1%, p=0.022) but were less likely to have associated LCIS (64.0 versus 74.2%, p=0.004). PR status was not associated with Ki67, BMI, lymphovascular invasion, local therapy, or surgical margins. In a Cox proportional hazards model adjusting for age, stage, grade, pleomorphic histology, and chemotherapy use, ER category was not associated with EFS but both PR negative and PR low status each had significantly worse EFS compared to PR ≥20% (HR 3.5, 95% CI 1.8-6.7, p< 0.001 for PR negative, and HR 2.0, 95% CI 1.1-3.5, p=0.015 for PR low). The estimated cumulative 5-year EFS for patients with ER low, medium, and high tumors was 87.1%, 93.4%, and 90.1% respectively. The estimated cumulative 5-year EFS for patients with PR negative, low, and high tumors was 78.9%, 90.2%, and 92.7% respectively. Conclusions: Using ILC-specific categories for ER expression, we found associations between ER category and clinicopathologic variables but not with EFS. In contrast, PR negative and low status was associated with worse EFS. These findings highlight the importance of exploring the spectrum of ER/PR activity within ILC, a classically strongly hormone receptor-positive tumor type, using more quantitative methods. Citation Format: Elle Clelland, Harriet T. Rothschild, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, Mary Kathryn Abel, W. Fraser Symmans, Jo Chien, Christopher J. Schwartz, Rita Mukhtar. Quantifying estrogen and progesterone receptor status in early-stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series [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 P2-03-16.
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- 2023
29. Emerging immunotherapeutic strategies for the treatment of breast cancer
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Veronica Mariotti, A. Jo Chien, Laura A. Huppert, and Hatem Soliman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Intratumoral Therapy ,Cancer ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,Clinical trial ,Breast cancer ,Immune system ,Internal medicine ,medicine ,business - Abstract
Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.
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- 2021
30. Lapatinib: New Directions in HER2 Directed Therapy for Early Stage Breast Cancer
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Jo Chien, A., Rugo, Hope S., Castiglione, Monica, editor, and Piccart, Martine J., editor
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- 2009
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31. Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer before chemo-endocrine therapy
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Sonal Shad, William Fraser Symmans, Debu Tripathy, Lamorna Brown-Swigart, LJ Esserman, Jane Perlmutter, V. Valero, Rebekah Gould, Gregor Krings, Judy C. Boughey, Jodi M. Carter, M. van der Noordaa, Gillian L. Hirst, L.J. van 't Veer, Christina Yau, Douglas Yee, Lajos Pusztai, Tufia C. Haddad, Kathy S. Albain, Molly Klein, Lili Du, MC Liu, Rita Nanda, Claudine Isaacs, Richard Schwab, Amy Jo Chien, Donald A. Berry, Rachel M. Layman, AM DeMichele, Isabelle Bedrosian, Sara J. Venters, and Nola M. Hylton
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Receptor, ErbB-2 ,medicine.medical_treatment ,Breast Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,MammaPrint ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Stage (cooking) ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Proportional hazards model ,Hazard ratio ,Cancer ,Hematology ,Prognosis ,medicine.disease ,Hormones ,Neoadjuvant Therapy ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,Receptors, Progesterone ,business - Abstract
BACKGROUND We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.
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- 2021
32. ACR11 modulates levels of reactive oxygen species and salicylic acid-associated defense response in Arabidopsis
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Singh, Shashi Kant, Sung, Tzu-Ying, Chung, Tsui-Yun, Lin, Shao-Yu, Lin, Sang-Chu, Liao, Jo-Chien, Hsieh, Wei-Yu, and Hsieh, Ming-Hsiun
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- 2018
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33. Dysfunctional chloroplasts up-regulate the expression of mitochondrial genes in Arabidopsis seedlings
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Liao, Jo-Chien, Hsieh, Wei-Yu, Tseng, Ching-Chih, and Hsieh, Ming-Hsiun
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- 2016
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34. Invasive Lobular Carcinoma of the Breast: Ongoing Trials, Challenges, and Future Directions
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A. Jo Chien and Rita A. Mukhtar
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Oncology ,0303 health sciences ,medicine.medical_specialty ,business.industry ,medicine.disease ,body regions ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Treatment targets ,Surgical oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Invasive lobular carcinoma ,Medicine ,Stage (cooking) ,skin and connective tissue diseases ,business ,030304 developmental biology - Abstract
Purpose of Review Invasive lobular carcinoma (ILC) is increasingly recognized as a distinct subtype of breast cancer with unique management challenges. We reviewed currently available clinical trials for patients with ILC. Recent Findings We describe the rationale for and study design of clinical trials for patients with both early stage and metastatic ILC. Molecular alterations specific to or enriched in ILC may serve as treatment targets. Summary ILC has specific features that may be treatment targets. Clinical trials for ILC are available and being developed.
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- 2021
35. Abstract PS13-20: Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage breast cancer
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Ron Bose, Maureen E. Trudeau, José A. García-Sáenz, Adam Brufsky, Arlene Chan, Gavin Marx, Debu Tripathy, M. Thirlwell, Daniel Hunt, Utpal Khambholja, Manuel Ruiz-Borrego, Naisargee Shah, Carlos H. Barcenas, A. Jo Chien, Leanne McCulloch, and Daniel Egle
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Cancer Research ,Loperamide ,medicine.medical_specialty ,business.industry ,medicine.disease ,Metastatic breast cancer ,Diarrhea ,Breast cancer ,Oncology ,Tolerability ,Internal medicine ,Neratinib ,Adjuvant therapy ,Medicine ,medicine.symptom ,business ,Adverse effect ,medicine.drug - Abstract
Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy and for patients with HER2+ metastatic breast cancer in the 3rd-line setting. Diarrhea, particularly in the first 1-2 months, is the main tolerability concern with neratinib and is common in the absence of proactive management. In the ExteNET trial, where no mandatory prophylaxis was used, the rate of grade 3 diarrhea was 40%, 34% of patients experienced at least 1 dose hold, and 17% of patients discontinued due to diarrhea. The CONTROL trial previously showed that pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or dose escalation (DE) reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Currently, antidiarrheal prophylaxis is initiated with the first dose of neratinib and used during the first 2 cycles of treatment (US PI). Updated findings from two DE cohorts in CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years with stage I-IIIc HER2+ breast cancer were treated with neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts including 2 dose-escalation cohorts: DE1 (neratinib 120 mg/day on days 1-7, 160 mg/day on days 8-14, then 240 mg/day to day 365) + loperamide as needed (PRN); and DE2 (neratinib 160 mg/day on days 1-14, 200 mg/day on days 15-28, then 240 mg/day to day 365) + loperamide PRN. Adverse events were graded per NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: May 1, 2020. Results: Complete data for DE1 (60 patients) and interim data for the ongoing DE2 (60 patients) are presented. All patients in DE1 were off study and 40 (66.7%) of patients remained on treatment in the ongoing DE2. The median treatment duration for DE1 was 12.0 months (IQR 11.1-12.0) and for DE2 was 3.7 months (IQR 1.6-9.1). Overall, 48% and 57% of DE1 and DE2 patients, respectively, had prior pertuzumab; 0% and 3%, respectively, had prior T-DM1. The majority of patients in both DE1 and DE2 dose-escalated to 240 mg on planned schedule. The incidence of grade ≥3 diarrhea was 13.3% in DE1 and 20.0% in DE2. The median cumulative duration of grade ≥3 diarrhea over the entire 12-month treatment period was 3 days (range 1-6 days) for DE1 and 2 days (range 1-7 days) for DE2. In both DE1 and DE2, 7 patients (11.7%) had at least one dose hold while on study (none during escalation phase in DE1 and 4 during escalation phase in DE2). In both DE1 and DE2, 2 (3.3%) patients discontinued neratinib because of diarrhea (1 during escalation phase in each cohort). Updated data for the DE2 cohort will be presented. Conclusions: Adoption of neratinib DE reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET. DE1 was associated with low rates of dose holds and diarrhea-related discontinuations compared with all previously mandated prophylaxis strategies investigated in CONTROL and with ExteNET. Together these results show improved tolerability of neratinib with DE and suggest that DE combined with loperamide PRN may allow patients to stay on neratinib for the recommended period of time. Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=60)On neratinib treatment, %066.7Median duration of treatment, months12.03.7Diarrhea, %Grade 140.041.7Grade 245.033.3Grade 313.320.0Grade 400Discontinuation rate due to diarrhea, %3.33.3At least one dose hold due to diarrhea, %11.711.7 Citation Format: Manuel Ruiz-Borrego, Arlene Chan, Gavin Marx, Adam Brufsky, A Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Daniel Hunt, Utpal Khambholja, Leanne McCulloch, Naisargee Shah, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage 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 PS13-20.
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- 2021
36. Abstract PS2-19: Circulating tumor cell (CTC) enumeration in a phase II trial of pazopanib in addition to endocrine therapy in patients with hormone resistant advanced breast cancer (ABC)
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A. Jo Chien, Travis Deal, Chiara A. Wabl, Mark Jesus M. Magbanua, Melanie Catherine Majure, Hope S. Rugo, Jonathan R. Renslo, Michelle E. Melisko, John W. Park, Andrei Goga, Mark M. Moasser, Ozge Gumusay, and Jimmy Hwang
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Letrozole ,Anastrozole ,medicine.disease ,Metastatic breast cancer ,Pazopanib ,Breast cancer ,Circulating tumor cell ,Internal medicine ,Medicine ,Progression-free survival ,business ,Progressive disease ,medicine.drug - Abstract
Background: CTCs are detectable in approximately 50% of pts with metastatic breast cancer, and elevated CTC levels are an independent negative prognostic factor. CTCs have been shown to play a valuable role in predicting outcomes in pts with ABC treated with chemotherapy or endocrine therapy. This phase II trial was conducted to evaluate the clinical benefit (CB) of pazopanib, a VEGF receptor tyrosine kinase inhibitor (TKI) combined with nonsteroidal aromatase inhibitors (NSAIs) in pts with ABC resistant to NSAIs. As an exploratory analysis, we hypothesized that CTC levels might be correlated with response to pazopanib plus endocrine therapy. Methods: Eligibility included postmenopausal women with hormone receptor positive (HR+) ABC and progressive disease after at least one month of NSAIs. Treatment was pazopanib 800 mg/day plus either letrozole or anastrozole. The primary endpoint was clinical benefit rate at 12 weeks (CBR12, wks). Secondary endpoints included progression free survival (PFS), safety, and the impact of pazopanib and NSAI on CTCs. A CBR of 20% was considered a clinically meaningful comparison to the expected CBR of Results: 32 pts were enrolled; 28 are evaluable for study endpoints. The median age was 58 years (range: 41-77). Pts were heavily pre-treated, with a median of 2 prior hormone therapies (range 1-6) and 1 prior chemotherapy (range 0-8). 8 pts (28.6%) stopped treatment due to adverse events, and 6 pts progressed before wk 12. CBR12 was 46.4% (12 SD, 1 PR), and CBR24 was 25% (5 SD, 2 PR). Safety has been presented (ASCO 2020). Median PFS was 20 wks, and median PFS for pts with CBR12 was 24 wks. Five (22%) of 23 pts with CTC data were CTC-positive (5 CTC/7.5 mL). There was no significant association between CBR12 and CTC status at baseline, or between CBR12 and change in CTC status (baseline to 4 wks after initiation of treatment). 7 pts had non-CBR12 and CTC data; 4 pts (n=4/7; 57%) were CTC positive at either baseline, week 4 or both. 11 pts had CBR12 and CTC data; all patients were CTC negative at baseline and remained negative at 4 wks. 7 pts had PFS >6 months (24, 32, 36, 36, 48, 184 and 274 wks), and 6 had CTC data: all were CTC-negative at baseline and 4 wks, then remained negative at 12 wks. Based on baseline values only, CTC-positive pts had a shorter median PFS compared to CTC-negative pts, but the difference was not statistically significant (11 wks vs 14 wks, p=0.18). Persistently CTC negative patients had significantly longer PFS compared to patients who were CTC positive at any time during study treatment (36 wks vs 11 wks, p=0.01). Conclusions: The addition of pazopanib to NSAIs resulted in a CBR12 of 46.4%, and a CBR24 of 25% in pts with heavily pre-treated ABC resistant to NSAIs. These results support clinical efficacy of antiangiogenic TKI in HR+ ABC and suggest benefit in hormone resistant disease. Consistently negative CTCs correlated with response and response duration. PFS was significantly longer in patients who were consistently CTC negative, further defining the prognostic role of CTCs in HR+ ABC. (NCT01466972) Citation Format: Ozge Gumusay, Mark Jesus M. Magbanua, Melanie C. Majure, Travis Deal, Jonathan R. Renslo, Chiara A. Wabl, Michelle E. Melisko, A. Jo Chien, Andrei Goga, Mark M. Moasser, John W. Park, Jimmy Hwang, Hope S. Rugo. Circulating tumor cell (CTC) enumeration in a phase II trial of pazopanib in addition to endocrine therapy in patients with hormone resistant advanced breast cancer (ABC) [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 PS2-19.
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- 2021
37. Abstract PS2-07: Outcomes associated with disseminated tumor cells at surgery after neoadjuvant chemotherapy in high-risk early stage breast cancer: The I-SPY SURMOUNT study
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Laura van 't Veer, E. Paul Wileyto, Erica L. Carpenter, Judy C. Boughey, Lamorna Brown Swigart, Mark Jesus M. Magbanua, Amy S. Clark, Stephanie S. Yee, Heather Beckwith, A. Jo Chien, Angela DeMichele, Christina Yau, John W. Park, Jane Perlmutter, Anne M. Wallace, Lewis A. Chodosh, HS Han, Lauren J. Bayne, Shannon DeLuca, Laura J. Esserman, and Minetta C. Liu
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Tumor cells ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,Stage (cooking) ,business - Abstract
Background: Disseminated tumor cells (DTCs) in bone marrow detected after treatment may represent occult residual disease. We enumerated DTCs after neoadjuvant chemotherapy (NACT) in patients (pts) diagnosed with high-risk early stage breast cancer and examined the relationship of these cells with response and survival. Methods: I-SPY SURMOUNT is a sub-study of the I-SPY 2 TRIAL (NCT01042379). Pts enrolled on I-SPY 2, who signed consent for this sub-study, had bone marrow aspirates (BMA) collected after NACT at the time of surgery. DTCs were isolated and enumerated from BMA using immunomagnetic enrichment/flow cytometry (IE/FC). DTCs were defined as EPCAM-positive and CD45-negative nucleated cells. Samples were considered positive using a predetermined threshold of >4 DTCs per mL (Magbanua et al, unpublished data). Pathologic response was assessed using the residual cancer burden (RCB) method at local sites, and pts underwent standard adjuvant therapy if indicated and follow up for recurrence events and death. Relationship of DTCs with clinicopathologic variables was examined using Chi-squared test. Group means were compared using t tests. The log-rank test was used to compare survival curves. Results: A total of 73 patients were enrolled, 51 of whom had successful DTC assessment. The median DTC per mL was 4 (interquartile range 1.2-11.6). 24/51 (47%) were DTC-positive. Clinical characteristics by DTC status are shown in the table. DTC-positive pts were significantly younger (p=0.02) and had larger pretreatment tumors (longest diameter by magnetic resonance imaging) compared to DTC-negative pts (p=0.032). DTCs were not associated with receptor subtype. Thirty pts (41%) achieved a pathologic complete response (pCR). DTCs were not associated with pCR (p= 0.166); however, DTC-positive patients were significantly more likely to have residual cancer (RCB-II/III) after NACT compared to DTC-negative patients (OR 3.3, p=0.037). Median follow up of this cohort was 2.8 years (range: 0.9-4.8). Interim survival analysis showed that DTCs were not significantly correlated with EFS (p=0.6) or DRFS (p=0.41). Conclusions: Detection of DTCs at surgery after NACT is significantly more common in young patients, those with larger tumors, and those with residual disease at surgery. While these associations suggest higher risk for later recurrence, larger studies and longer follow up are necessary to determine if DTCs add prognostic value over pathologic evaluation alone for pts receiving NACT. Citation Format: Mark Jesus M Magbanua, Laura van 't Veer, Amy Clark, A. Jo Chien, Judy Boughey, Heather Han, Anne Wallace, Heather Beckwith, Minetta Liu, Christina Yau, E. Paul Wileyto, Lamorna Brown Swigart, Jane Perlmutter, Lauren Bayne, Shannon Deluca, Stephanie Yee, Erica Carpenter, Laura Esserman, John Park, Lewis Chodosh, Angela DeMichele. Outcomes associated with disseminated tumor cells at surgery after neoadjuvant chemotherapy in high-risk early stage breast cancer: The I-SPY SURMOUNT study [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 PS2-07.
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- 2021
38. Abstract PD1-10: Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL
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HS Han, Christina Yau, Jane Perlmutter, Amy Wilson, Heather Beckwith, Anne M. Wallace, Tara Sanft, Ashish Sanil, Erica Stringer-Reasor, Laura J. Esserman, Zahi Mitri, Donald A. Berry, Rita Nanda, Claudine Isaacs, Alexandra Thomas, Kevin Kalinsky, Hope S. Rugo, Michelle E. Melisko, A. Jo Chien, Smita Asare, W. Fraser Symmans, Judy C. Boughey, Douglas Yee, Laura J. van't Veer, Kathy S. Albain, Amy S. Clark, Julie E. Lang, Anthony D. Elias, Nola M. Hylton, Angela DeMichele, Shi Wei, and Richard Schwab
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Intention-to-treat analysis ,Cyclophosphamide ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,MammaPrint ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,business ,Neoadjuvant therapy ,medicine.drug - Abstract
Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [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 PD1-10.
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- 2021
39. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival
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Amy L. Delson, Gillian L. Hirst, Amy Jo Chien, Bernhard Zimmermann, L.J. van 't Veer, Alexey Aleshin, Denise M. Wolf, Svetlana Shchegrova, Raheleh Salari, AM DeMichele, Laura J. Esserman, H. Pawar, Mark Jesus M. Magbanua, Himanshu Sethi, Antony Tin, S Asare, MC Liu, Lamorna Brown Swigart, Debu Tripathy, Maggie C. Louie, C-Hj Lin, Paul Billings, Christina Yau, and H.-T. Wu
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0301 basic medicine ,Oncology ,Neoplasm, Residual ,medicine.medical_treatment ,Circulating Tumor DNA ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Cancer ,circulating tumor DNA ,screening and diagnosis ,Tumor ,Hazard ratio ,Hematology ,Neoadjuvant Therapy ,Detection ,Paclitaxel ,Residual ,030220 oncology & carcinogenesis ,neoadjuvant chemotherapy ,medicine.medical_specialty ,Anthracycline ,Oncology and Carcinogenesis ,Breast Neoplasms ,Article ,pathologic complete response ,03 medical and health sciences ,breast cancer ,Breast cancer ,Clinical Research ,Internal medicine ,Biomarkers, Tumor ,Genetics ,Humans ,Oncology & Carcinogenesis ,Survival analysis ,Chemotherapy ,business.industry ,Surrogate endpoint ,Prevention ,Odds ratio ,medicine.disease ,4.1 Discovery and preclinical testing of markers and technologies ,Good Health and Well Being ,030104 developmental biology ,chemistry ,Mutation ,Neoplasm ,business ,Biomarkers - Abstract
Author(s): Magbanua, MJM; Swigart, LB; Wu, H-T; Hirst, GL; Yau, C; Wolf, DM; Tin, A; Salari, R; Shchegrova, S; Pawar, H; Delson, AL; DeMichele, A; Liu, MC; Chien, AJ; Tripathy, D; Asare, S; Lin, C-HJ; Billings, P; Aleshin, A; Sethi, H; Louie, M; Zimmermann, B; Esserman, LJ; van 't Veer, LJ | Abstract: BackgroundPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence.Patients and methodsCell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.ResultsAt T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, Pn= 0.012). After NAC, all patients who achieved pCR were ctDNA negative (nn= 17, 100%). For those who did not achieve pCR (nn= 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).ConclusionsLack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
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- 2021
40. Evaluation of the business operation performance of the listing companies by applying TOPSIS method.
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Tien-Chin Wang and Jo-Chien Hsu
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- 2004
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41. Abstract GS5-03: Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL
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Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, and null I-SPY Investigators
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Cancer Research ,Oncology - Abstract
Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [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 GS5-03.
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- 2023
42. Abstract PD11-01: PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL
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Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, and I-SPY Investigators
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Cancer Research ,Oncology - Abstract
Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [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 PD11-01.
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- 2023
43. Use of 18F-FDG PET/CT as an Initial Staging Procedure for Stage II–III Breast Cancer: A Multicenter Value Analysis
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Heather Beckwith, Flora Varghese, Andres Forero-Torres, Michelle E. Melisko, Robert R. Flavell, Claudine Isaacs, Laura J. Esserman, Colby J. Hyland, Christina Yau, William Varnado, Gillian L. Hirst, A. Jo Chien, Douglas Yee, and Katia E. Khoury
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medicine.medical_specialty ,business.industry ,Stage ii ,medicine.disease ,Asymptomatic ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Staging procedure ,medicine ,Abdomen ,In patient ,Fdg pet ct ,Radiology ,Stage (cooking) ,medicine.symptom ,business - Abstract
Background: Metastatic staging imaging is not recommended for asymptomatic patients with stage I–II breast cancer. Greater distant metastatic disease risk may warrant baseline imaging in patients with stage II–III with high-risk biologic subtypes. NCCN Guidelines recommend considering CT of the chest, abdomen, and pelvis (CT CAP) and bone scan in appropriate patients. CT CAP and bone scan are considered standard of care (SoC), although PET/CT is a patient-centered alternative. Methods: Data were available for 799 high-risk patients with clinical stage II–III disease who initiated screening for the I-SPY2 trial at 4 institutions. A total of 564 complete records were reviewed to compare PET/CT versus SoC. Costs were determined from the payer perspective using the national 2018 Medicare Physician Fee Schedule and representative reimbursements to the University of California, San Francisco (UCSF). Incremental cost-effectiveness ratio (ICER) measured cost of using PET/CT per percent of patients who avoided a false-positive (FP). Results: The de novo metastatic disease rate was 4.6%. Imaging varied across the 4 institutions (PP=.0009). Mean time between incidental finding on baseline imaging to FP determination was 10.8 days. Mean time from diagnosis to chemotherapy initiation was 44.3 days with SoC versus 37.5 days with PET/CT (P=.0001). Mean cost per patient was $1,132 (SoC) versus $1,477 (PET/CT) using the Medicare Physician Fee Schedule, with an ICER of $31. Using representative reimbursements to UCSF, mean cost per patient was $1,236 (SoC) versus $1,073 (PET/CT) for Medicare, and $3,083 (SoC) versus $1,656 (PET/CT) for a private payer, with ICERs of −$15 and −$130, respectively. Conclusions: Considerable variation exists in metastatic staging practices. PET/CT reduced FP risk by half and decreased workup of incidental findings, allowing for earlier treatment start. PET/CT may be cost-effective, and at one institution was shown to be cost-saving. Better alignment is needed between hospital pricing strategies and payer coverage policies to deliver high-value care.
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- 2020
44. The 21-Gene Recurrence Score in Clinically High Risk Lobular and Ductal Breast Cancer: A National Cancer Database Study
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Mary Kathryn Abel, Amy S Shui, A. Jo Chien, Hope S. Rugo, Michelle Melisko, Frederick Baehner, and Rita A. Mukhtar
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skin and connective tissue diseases - Abstract
Purpose: To evaluate whether patients with ILC are more likely to have discordant clinical and genomic risk than those with IDC when using the 21-gene recurrence score (RS), and to assess overall survival outcomes of patients with 1-3 positive nodes and RS ≤ 25 with and without chemotherapy, stratified by histology.Methods: We performed a cohort study using the National Cancer Database and included patients with hormone receptor positive, HER2 negative, stage I-III invasive breast cancer who underwent 21-gene RS testing. Our primary outcome was rate of discordant clinical and genomic risk status by histologic subtype. Propensity score matching was used to compare 60-month overall survival in individuals with 1-3 positive nodes and RS £ 25 who did and did not receive chemotherapy.Results: 186,867 patients were included in our analysis, including 37,685 (20.2%) patients with ILC. There was a significantly higher rate of discordant clinical and genomic risk in patients with ILC compared to IDC. Among patients with 1-3 positive nodes and RS ≤ 25, there was no significant difference in survival between those who did and did not receive chemotherapy in the IDC or ILC cohorts. Unadjusted exploratory analyses of patients under age 50 with 1-3 positive nodes and RS ≤ 25 showed improved overall survival in IDC patients who received chemotherapy, but not among those with ILC.Conclusion: Our findings highlight the importance of lobular-specific tools for stratifying clinical and genomic risk, as well as the need for histologic subtype-specific analyses in randomized trials.
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- 2022
45. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial
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Rashmi Krishna Murthy, Amelia Zelnak, Giuseppe Curigliano, Carey K. Anders, Elisavet Paplomata, Mafalda Oliveira, Eric P. Winer, Virginia F. Borges, Karen A. Gelmon, Alison Conlin, Xuebei An, Michael DiGiovanna, Sibylle Loibl, Alicia Okines, Sara A. Hurvitz, Ruth O'Regan, Philippe L. Bedard, Andrew M Wardley, Lisa A. Carey, Thomas Bachelot, Jo Al Mayor, David Cameron, A. Jo Chien, Nan Lin, Sherene Loi, Vandana G. Abramson, Suzanne McGoldrick, Erika Hamilton, Volkmar Mueller, Institut Català de la Salut, [Lin NU] Dana-Farber Cancer Institute, Boston, MA, USA. [Borges V] University of Colorado Cancer Center, Aurora, CO, USA. [Anders C] Duke Cancer Institute, Durham, NC, USA. [Murthy RK] MD Anderson Cancer Center, Houston, TX, USA. [Paplomata E] Carbone Cancer Center/University of Wisconsin, Madison, WI, USA. [Hamilton E] Sarah Cannon Research Institute/Tennessee Oncology–Nashville, Nashville, TN, USA. [Oliveira M] Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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0301 basic medicine ,Oncology ,Cancer Research ,Pyridines ,Receptor, ErbB-2 ,medicine.medical_treatment ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,law.invention ,ErbB-2 ,0302 clinical medicine ,Randomized controlled trial ,Mama - Càncer ,law ,Trastuzumab ,Antineoplastic Combined Chemotherapy Protocols ,Other subheadings::/therapeutic use [Other subheadings] ,Young adult ,Oxazoles ,Cancer ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Brain Neoplasms ,Middle Aged ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Receptor ,medicine.drug ,Adult ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Breast Neoplasms ,Capecitabine ,03 medical and health sciences ,Young Adult ,Breast cancer ,Double-Blind Method ,Clinical Research ,Internal medicine ,RAPID COMMUNICATIONS ,Breast Cancer ,medicine ,Humans ,Oncology & Carcinogenesis ,terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Aged ,Medicaments antineoplàstics - Ús terapèutic - Eficàcia ,business.industry ,Otros calificadores::/uso terapéutico [Otros calificadores] ,Neurosciences ,Evaluation of treatments and therapeutic interventions ,Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,Radiation therapy ,030104 developmental biology ,Clinical research ,Quinazolines ,business - Abstract
PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.
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- 2020
46. Abstract P3-09-11: Modulation of the immune microenvironment in high risk DCIS
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Cliff Hoyt, Jo Chien, Emma McCune, Scott R. VandenBerg, Tristan Loveday, Jasmine Wong, Michael J. Campbell, Harriet Rothschild, Jennifer Bolen, and Laura J. Esserman
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Cancer Research ,business.industry ,T cell ,medicine.medical_treatment ,Pembrolizumab ,Immunotherapy ,Immune checkpoint ,medicine.anatomical_structure ,Immune system ,Oncology ,Cancer research ,medicine ,Cytotoxic T cell ,business ,B cell ,CD8 - Abstract
Background. Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. Features of DCIS that are associated with a high risk of a subsequent event include large size (> 5 cm), high grade, comedo necrosis, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates in DCIS are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high risk DCIS could potentially alter disease progression. Objectives. The objectives of this study were: 1). to define dose limiting toxicities, tolerability, and feasibility of intralesional injection of an immune checkpoint inhibitor (pembrolizumab) into DCIS; and 2). to determine response rate as measured by an increase in total T cells or CD8+ T cells from baseline to post treatment. Methods. Study participants received 2 intralesional injections of pembrolizumab, 3 weeks apart, with surgery approximately 3 weeks after the 2nd dose. Multiplex immunofluorescence analyses were used to compare immune cell populations in pre-treatment biopsies to post-treatment surgical specimens. Tissue samples were stained with two 6-plex immune panels using Opal immunofluorescence reagents (Perkin Elmer) on a fully automated Ventana Discovery platform, imaged with a Vectra 3 system and analyzed with inForm software (Perkin Elmer). Results. The intralesional injections were well tolerated and there were no systemic toxicities observed. Multiplex immunofluorescence analyses demonstrated significant increases in total T cells, as well as cytotoxic CD8+ T cells, following therapy. We also observed a significant positive correlation between the change (pre- vs. post-therapy) in Ki67+ T cells (proliferating T cells) with the increase in total T cells, suggesting that immune checkpoint inhibition removed the “brakes” from the T cells, allowing them to proliferate. Changes in macrophage, B cell, and Treg numbers pre- vs. post-therapy were not significant. Despite an increase in T cell infiltrates, there were no measurable indicators of an anti-tumor response: no reduction in lesion size by MRI, no reduction in proliferation of DCIS cells (Ki67 staining), and no increase in cell death (cleaved caspase 3 staining). Spatial analyses indicated that in most cases the T cell expansion (both total T cells and CD8+ T cells) occurred predominantly in the stroma, not among the DCIS cells in the ducts. Conclusions. We met the objectives of our study: 1). we demonstrated the safety and feasibility of intralesional injection of an immune checkpoint inhibitor (pembrolizumab) in high risk DCIS; and 2). we demonstrated that local immunotherapy resulted in the local proliferation/expansion of T cells. However we did not observe any change in the size of the lesions by MRI. In addition, there was no evidence for T cell killing at the cellular level, suggesting that even though there was an expansion of T cells, there are other factors at play such as immune exclusion or possibly immunosuppression of their killing ability. These results suggest that combination of pembrolizumab with another agent(s) will be needed to achieve a more complete response. Citation Format: Michael Campbell, Jasmine Wong, Emma McCune, Harriet Rothschild, Tristan Loveday, Jennifer Bolen, Cliff Hoyt, Scott VandenBerg, Jo Chien, Laura Esserman. Modulation of the immune microenvironment in high risk DCIS [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 P3-09-11.
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- 2020
47. Abstract P5-14-03: Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL trial
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Leanne McCulloch, Sara A. Hurvitz, Manuel Ruiz-Borrego, A. Jo Chien, Arlene Chan, Debu Tripathy, Daniel Hunt, Gavin Marx, Carlos H. Barcenas, and Cynthia Farrell
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Loperamide ,business.industry ,Colestipol ,medicine.disease ,03 medical and health sciences ,Diarrhea ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,Neratinib ,medicine ,Adjuvant therapy ,medicine.symptom ,business ,Adverse effect ,medicine.drug - Abstract
Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy. Diarrhea is the main tolerability concern with neratinib and is common in the absence of proactive management. The CONTROL study (Clinicaltrials.gov: NCT02400476) is investigating the effectiveness of rationally structured antidiarrheal prophylaxis or neratinib dose escalation in the prevention of neratinib-associated diarrhea. CONTROL includes antidiarrheal prophylactic regimens with loperamide either alone or in combination with budesonide (locally acting corticosteroid) or colestipol (bile acid sequestrant), as well as two different neratinib dose-escalation schedules. Updated findings from CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase II study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer were treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide prophylaxis; 3) colestipol + loperamide prophylaxis; 4) colestipol + loperamide prn; 5) neratinib dose escalation + loperamide prn (two cohorts). Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: 17 June 2019. Results: A total of 514 patients have been enrolled. At the cut-off date, study treatment had been completed by 100% of patients in all cohorts except for the two neratinib dose-escalation cohorts (the colestipol + loperamide prn cohort had just 1 patient continuing treatment as of the cut-off date). All preventive strategies reduced the incidence of grade 3 diarrhea (Table) compared with that seen in ExteNET (historical control: 39.9%). Median cumulative duration of grade 3 diarrhea across the study cohorts ranged from 2-5 days for the entire 12-month treatment period. The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for Cohort 1. The majority of adverse events (including diarrhea) leading to treatment discontinuation occurred early while on treatment, primarily during the first or second cycle. Table. Characteristics of treatment-emergent diarrheaLoperamide (n=137)Budesonide + loperamide (n=64)Colestipol + loperamide (n=136)Colestipol + loperamide prn (n=104)Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=13)On neratinib treatment, %0001.0a85.084.6Diarrhea, %Grade 124.125.027.930.841.723.1Grade 224.832.834.632.738.346.2Grade 330.728.120.631.715.07.7Grade 4000000Median cumulative duration, days (range)Grade ≥25.0 (1-400)6.0 (1-117)4.0 (1-371)8.0 (1-375)5.0 (1-28)2.0 (1-6)Grade 33.0 (1-93)2.5 (1-6)3.5 (1-22)3.0 (1-55)2.0 (1-5)5.0 (5-5)Discontinuation (due to a diarrhea TEAE), %20.410.94.47.73.30Hospitalization (due to a diarrhea TEAE), %1.500000aAs of the data cut-off, the final patient in the colestipol + loperamide prn cohort had completed 1 year of neratinib treatment but had not yet had the final study visit. Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1-2 cycles reduces the incidence, severity and duration of neratinib-associated diarrhea. These strategies reduce the rate of neratinib discontinuation due to diarrhea, allowing patients to receive the benefits of 1 year of extended adjuvant neratinib therapy. Early findings with escalating the dose of neratinib over the first 2-4 weeks of treatment are promising. Updated data for the two neratinib dose-escalation cohorts will be presented at the meeting. Citation Format: Arlene Chan, Sara A Hurvitz, Gavin Marx, Manuel Ruiz-Borrego, Cynthia Farrell, Daniel Hunt, Leanne McCulloch, A Jo Chien, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL 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 P5-14-03.
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- 2020
48. Abstract P2-20-02: Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints
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Michelle E. Melisko, Kirsten K. Edmiston, HS Han, W. Fraser Symmans, Gregor Krings, Molly Klein, Rita Nanda, Claudine Isaacs, Rebecca K. Viscusi, Sunati Sahoo, David M. Euhus, Jeffrey B. Matthews, Angela DeMichele, Erica Stringer-Reasor, Qamar J. Khan, Laura J. van't Veer, Tara Sanft, Christina Yau, Donald A. Berry, Richard Schwab, Janice Lu, Jane Perlmutter, A. Jo Chien, Donald W. Northfelt, Anne M. Wallace, Zaha Mitri, Jane L. Meisel, Julie E. Lang, Jodi M. Carter, Lajos Pusztai, Hope S. Rugo, Rachel L. Yung, Erin D. Ellis, Anthony D. Elias, Laila Khazai, Kathy S. Albain, Yunn-Yi Chen, Nola M. Hylton, Amy S. Clark, Laura J. Esserman, Christos Hatzis, Judy C. Boughey, Douglas Yee, Kimberly Cole, and Dina Kokh
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Oncology ,Cancer Research ,medicine.medical_specialty ,Proportional hazards model ,medicine.medical_treatment ,Incidence (epidemiology) ,Hazard ratio ,Cancer ,Biology ,medicine.disease ,Breast cancer ,Internal medicine ,Cohort ,medicine ,Neoadjuvant therapy ,Sanctuary site - Abstract
Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [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 P2-20-02.
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- 2020
49. Abstract P3-11-02: Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 trial
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Amy Wilson, Erica Stringer-Reasor, Jane Perlmutter, Christina Yau, Donald A. Berry, Kevin Kalinsky, Ashish Sanil, Kathy S. Albain, Hope S. Rugo, Teresa Helsten, Amy S. Clark, Laura J. Esserman, Erin D. Ellis, Angela DeMichele, Richard Schwab, Anthony D. Elias, Smita Asare, Nola M. Hylton, Michelle E. Melisko, Claudine Isaacs, Anne M. Wallace, Judy C. Boughey, Ruby Singhrao, Janice Lu, Douglas Yee, Julie E. Lang, Shelly S. Lo, Laura J. van't Veer, A. Jo Chien, and W. Fraser Symmans
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Oncology ,Cancer Research ,Patritumab ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Regimen ,Breast cancer ,MammaPrint ,Trastuzumab ,Internal medicine ,medicine ,Clinical endpoint ,business ,Neoadjuvant therapy ,medicine.drug - Abstract
Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 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 P3-11-02.
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- 2020
50. Abstract P3-09-02: Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL
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Ruby Singhrao, Jane Perlmutter, Angela DeMichele, A. Jo Chien, Christina Yau, HS Han, Donald A. Berry, Patricia A. Robinson, W. Fraser Symmans, Kevin Kalinsky, Laura J. Esserman, Richard Schwab, Anne M. Wallace, Erica Stringer-Reasor, Kathy S. Albain, Patricia K Haugen, Tara Sanft, Amy S. Clark, Ashish Sanil, Smita Asare, Laura J. van't Veer, Kathleen Kemmer, Hope S. Rugo, Amy Wilson, Janice Lu, Julie E. Lang, Minetta C. Liu, Anthony D. Elias, Nola M. Hylton, Rita Nanda, Claudine Isaacs, Douglas Yee, Michelle E. Melisko, and Judy C. Boughey
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,HER2 negative ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,Stage (cooking) ,business ,Neoadjuvant therapy - Abstract
Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility ( Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 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 P3-09-02.
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- 2020
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