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Background: In ER+ breast cancer (BC) models, Aurora A kinase (AURKA) activation is associated with expansion of CD44+/CD24low/- tumor initiating cells, down-regulation of ERα, and endocrine therapy resistance. Alisertib, a selective AURKA inhibitor, can restore ERα expression and endocrine sensitivity. Early phase studies evaluating alisertib alone or with fulvestrant for ER+ metastatic BC (MBC) demonstrated a favorable safety profile and promising antitumor activity [Haddad, Breast Cancer Res Treat. 2018]. A phase II trial was conducted to determine if the addition of fulvestrant to alisertib improved objective response rate (ORR) and to assess clinical activity of alisertib alone or with fulvestrant in patients (pts) with prior fulvestrant and CDK 4/6 inhibitor (CDK 4/6i). Methods: Pts were randomized 1:1 to Arm A, alisertib (50 mg PO BID Days 1-3, 8-10, 15-17 q 28 days) or Arm B, alisertib with fulvestrant (500 mg IM Day 1, 15 for Cycle 1 and q 28 days thereafter). Eligibility included postmenopausal women, history of ER+ BC, prior fulvestrant, ≤ 2 prior chemotherapy lines, and measurable disease. Stratification factors included prior CDK4/6i, ER level ( 6 cycles), overall survival, duration of response (DoR), and safety. Blood and tumor specimens were collected at baseline, end of Cycle 1, and progression. Results: Pts enrolled July 2017 - November 2019 with 118 pre-registered, 96 registered, and 90 evaluable for the primary endpoint (Arm A: 45, Arm B: 45). Median age was 60 (range 33, 85). Nearly all received prior fulvestrant (n=89, 98.9%), aromatase inhibitor (n=83, 92.2%), and CDK4/6i (n=88, 97.8%). Most had secondary endocrine resistance (n=71, 78.9%). Pre-registration biopsy for ER was positive in 84 pts (86.7%) and negative in 6 pts (13.3%). More pts on Arm B had prior everolimus (A: 35.6%, B: 57.8%) and prior chemotherapy (A: 44.4%, B: 55.6%) for MBC. The ORR for alisertib and fulvestrant was 20.0% (90% CI: 10.9-32.3%), not significantly greater than alisertib alone 17.8% (90% CI: 9.2-29.8%). The 24-week CBR for Arm A was 42.2% (90% CI: 29.7-55.6%; n=19, including 7 PR) and Arm B was 31.1% (90% CI: 19.9-44.3%; n=14, including 8 PR). As of July 1, 2020, the median DoR was not reached in either arm. The median PFS time was 5.6 months (95% CI: 3.9 - 9.3) for Arm A and 5.1 months (95%CI: 3.8 - 7.6) for Arm B. Seventeen pts (18.9%) remain on treatment (A: 12, B: 5) having received at least 11 cycles (range up to 32+ cycles). At least one dose reduction was required for pts (A: 19, B: 18), most commonly due to neutropenia. The most common severe (grade ≥3) adverse events included neutropenia (n=19, 42.2% in each arm), anemia (A: 15.6%, B: 8.8%), and fatigue (n=5, 11.1% Arm B only). Pts discontinued therapy due to disease progression equally in each arm (n=28, 62.2%), however more pts on Arm B (n=12) than Arm A (n=5) discontinued therapy due to toxicity, refusal or other reasons. Conclusion: While the addition of fulvestrant to alisertib did not improve ORR, promising clinical activity with alisertib monotherapy was observed overall and notably for pts with endocrine and CDK 4/6i-resistant MBC. More severe toxicities and treatment discontinuation were observed in pts receiving combination therapy. Correlative blood (CTC/cfDNA) and tissue (AURKA, ERα, and stemness biomarkers) studies are underway. Citation Format: Tufia Haddad, Antonino D'Assoro, Vera Suman, Jodi Carter, Brendan McMenomy, Erica Mayer, Meghan Karuturi, Aki Morikawa, Paul Marcom, Claudine Isaacs, Sun Young Oh, Amy Clark, Ingrid Mayer, Khandan Keyomarsi, Roberto Leon-Ferre, Karthik Giridhar, Ciara O'Sullivan, Prema Peethambaram, Timothy Hobday, Minetta Liu, James Ingle, Matthew Goetz. Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-05.

BACKGROUND: We examined whether the National Comprehensive Cancer Network distress thermometer (DT), a patient-reported outcome measure, could be used to identify levels and causes of distress associated with racial/ethnic disparities in time to care among patients with breast cancer. METHODS: We identified women aged ≥18 years with stage O-IV breast cancer who were diagnosed in a single health system between January 2014 and July 2016. The baseline visit was defined as the first postdiagnosis, pretreatment clinical evaluation. Zero-inflated negative binomial (ZINB) regression (modeling non-zero DT scores and DT scores = 0) and logistic regression (modeling DT score ≥ 4, threshold for social services referral) were used to examine associations between baseline score (0 = none to 10 = extreme) and types of stressors (emotional, familial, practical, physical, spiritual) after adjustment for race/ethnicity and other characteristics. Linear regression with log transformation was used to identify predictors of time to evaluation and time to treatment. RESULTS: A total of 1029 women were included (median baseline DT score = 4). Emotional, physical, and practical stressors were associated with distress in both the ZINB and logistic models (all P < .05). Black patients (n = 258) were more likely to report no distress than Whites (n = 675; ZINB zero model odds ratio, 2.72; 95% CI, 1.68-4.40; P < .001) despite reporting a similar number of stressors (P = .07). Higher DT scores were associated with shorter time to evaluation and time to treatment while being Black and having physical or practical stressors were associated with delays in both (all P < .05). CONCLUSIONS: Patient-reported stressors predicted delays in time to care, but patient-reported levels of distress did not, with Black patients having delayed time to care despite reporting low levels of distress. We describe anticipatory, culturally responsive strategies for using patient-reported outcomes to address observed disparities.

PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.

Background: It has become increasingly clear that effective treatment of metastatic breast cancer (MBC) requires an in-depth understanding of the molecular differences between primary tumors and metastases. The AURORA US Network was established to collect primary breast cancer-metastasis pairs for multi-platform genomic profiling in order to identify the molecular drivers of metastatic disease. AURORA US has both a retrospective and prospective phase. This is the first report of the retrospective phase. Methods: Archived tissue samples from the primary tumor and at least one distant metastasis were retrospectively collected from 83 MBC patients. Following internal quality assessment, samples from 55 pts, including 105 distinct metastatic lesions, were subject to DNA low pass whole genome and exome sequencing, DNA methylation arrays, and RNA sequencing. Early analyses of these multi-platform data include: DNA methylation, tumor gene expression and microenvironmental signatures, somatic and germline variants, DNA copy number changes, and structural variants between breast primaries and matched metastases. Results: Median age at diagnosis was 49 years (25-76); 32 (58%) were Stage I or II at presentation, 27 (49%) had a family history of breast cancer, and 20 (36%) had a second breast primary. Median disease-free interval before developing MBC was 2 years (range 0-36, 5 patients presented with Stage IV). Median overall survival from initial presentation was 4 years (range 0-37). Median survival after developing MBC was 1 year (range 0-13), with a median of three treatments. Primary tissue samples were banked from 1977-2017 and metastases were banked from 1999-2017. Clinical phenotypes of the primaries included 27 HR+ (49%), 15 triple negative (TNBC, 27%), and 11 HER2+ (20%, 12 missing HER2 status). Intrinsic subtype distribution of the primaries included 17 Basal-like (31%), 17 Luminal A (31%), 7 Normal-like (13%), 5 HER2-enriched (9%), and 1 Luminal B, with 8 pending. All metastases from the Basal-like cases remained Basal-like, while metastases from luminal primaries tended to gain HER2-Enriched subtype features (5/18, p = 0.01). Overall, we identified significant metastasis-enriched alterations in metabolism pathways, an increase in proliferation, and the loss of differentiation signatures and immune infiltrates with progression; the latter being the most pronounced in brain metastases. The most frequent somatic mutations in this cohort were in TP53, NCOR1, and RUNX1. Interestingly, ERBB2, EGFR, and ATM were also mutated in ≥10% of the tumors sequenced. In almost all cases, CpG island hypermethylation was clonally present in the primary tumor and persisted stably in the majority of metastatic lesions. Promoter CpG island hypermethylation was also identified in some metastatic lesions at JAM3, an important cellular adhesion molecule,and this was accompanied by reduced mRNA expression. CONCLUSIONS: Collection of banked primary and metastatic tissue pairs identified a young MBC cohort with a high frequency of breast cancer family history and second breast primaries. Molecular characterization of luminal tumor pairs highlighted acquisition of aggressive traits including increased proliferation and loss of differentiation in the metastases. In contrast, basal-like pairs remained relatively unchanged, except for the loss of immune activation. Ongoing analyses to be presented include clonal heterogeneity and phylogeny, novel metastasis signature discovery, gene fusion, and endogenous retrovirus detection. Citation Format: Tari A King, Minetta C Liu, Marni B McClure, Toshinori Hinoue, Benjamin J Kelly, Chad J Creighton, Jay Bowen, Kristen Leraas, Robyn T Burns, Sara Coppens, Salma Rezk, Amy L Garrett, Justin M Balko, Joel S Parker, Ben H Park, Ian Krop, Carey Anders, Katherine A Hoadley, Julie Gastier-Foster, Mothaffar F Rimawi, Rita Nanda, Nancy U Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J Couch, Elaine R Mardis, Adrian V Lee, Uma Chandran, Peter W Laird, Susan G Hilsenbeck, Larry Norton, Andrea L Richardson, W. Fraser Symmans, Lisa A Carey, Antonio C Wolff, Nancy E Davidson, Charles M Perou, the AURORA US Network. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-08.

Background: Meta-analyses have demonstrated that young women ≤40 (YW) derive the most benefit from chemotherapy (EBCTCG, Lancet. 1998). Oncotype DX was designed to determine the benefit of chemotherapy in women with ER+/HER2-, node-negative (LN-) breast cancer based on recurrence score (RS). TAILORx reported clinically meaningful benefits in freedom-from-distant recurrence in women Methods: Using the National Cancer Data Base (NCDB), we identified individuals age 25) RS. Age categories were classified as ≤40, 41-50, and >50. Chi-square tests or Fisher’s exact tests were used to compare categorical variables. Logistic regression was used to estimate the association of RS score and age group with adjuvant chemotherapy use, after adjustment for known covariates. Kaplan-Meier curves were used to visualize unadjusted overall survival (OS), and Cox proportional hazards models were used to estimate adjusted OS. Results: 120,051 women were identified, of whom 4,781 were ≤40 years, 24,846 were 41-50, and 90,424 were >50. By age group, 20% of YW had a high RS compared to 12% of women age 41-50 and 15% of women >50 (p50 to receive chemotherapy (p Conclusions: High RS is more common in YW (≤40) than those age 41-50 or >50, and is associated with worse OS. YW with an int or low RS are more likely to receive chemotherapy despite unclear benefit. Chemotherapy was omitted in over half of YW with RS of 16-25, highlighting the uncertainty in clinical practice which will remain until further studies inform optimal systemic treatment specific to YW. 1. Sparano, J.A., et al., Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. New England Journal of Medicine, 2019. 380(25): p. 2395-2405. Citation Format: Sarah Sammons, Yi Ren, Jeremy Force, Oluwadamilola M. Fayanju, Laura H. Rosenberger, Jennifer K. Plichta, Gretchen Kimmick, Kelly Westbrook, Susan Dent, Carey Anders, Samantha M. Thomas, Terry Hyslop, E. S. Hwang, P. K. Marcom, Rachel A. Greenup. Characterization of oncotype DX recurrence score and chemotherapy utilization patterns in young women (≤40) with early stage ER+/HER-, lymph node negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-10.

Background: ROS1 is an important proto-oncogene involved in the development of various cancers and increased expression is a poor prognostic feature in breast cancer. Activation of the ROS1 tyrosine kinase receptor has been reported and is being targeted with several FDA approved small molecule inhibitors, primarily in lung cancer. However, the frequency and type of ROS1 alterations in breast cancer have not been fully explored. The purpose of this study was to identify the incidence and type of ROS1 genomic alterations occurring in breast cancer as a prelude to potentially targeting this protein in the setting of metastatic breast cancers that harbor these changes. Methods: We queried 21,125 breast cancer samples (~50% from distant metastatic sites) from the Foundation Medicine breast cancer database, 5,964 breast cancer samples from five publicly available breast cancer databases (MBC Project, INSERM, METABRIC, TCGA, MSK-IMPACT), and 217 breast cancer samples from Project GENIE v6.5 to identify the incidence of ROS1 alterations in breast cancer. We identified fusion partner genes and classified each alteration type into the following categories: fusion, rearrangement, short variant (missense or indel), or copy number variation. A computational approach was used to distinguish somatic from germline single nucleotide polymorphisms in the Foundation Medicine database (Sun et. al., 2018). PolyPhen2 and in vitro analyses were used to investigate the effect of ROS1 nonsynonymous mutations on the ROS1 protein. Using Foundation Medicine, we made associations with ROS1 alterations and receptor status, histologic subtype, metastatic site, tumor mutational burden, and co-occurring mutated genes. Estrogen receptor (ER) status was available for 2,371 samples. HER2 status and all other analyses were identified from the entire cohort. Results: The incidence of any ROS1 alteration across the Foundation Medicine breast cancer database, including variants of unknown significance, was 4.6% and ranged from 1.67% to 6.9% from the five publicly available breast cancer databases and Project GENIE. Foundation Medicine samples revealed 5 (0.024%) breast cancers with ROS1 fusions, 86 (0.41%) with rearrangements, 733 (3.47%) with short nucleotide variants, and 182 (0.86%) with copy number variations. ROS1 alterations occurred similarly in HER2, TNBC, and ER+ breast cancers, 5.24%, 4.5%, and 4.37%, respectively (ns, all p>0.2). Invasive ductal carcinoma, invasive lobular carcinoma, and metaplastic carcinoma harbored ROS1 alterations at 4.35%, 3.65%, and 4.36%, respectively (ns, all p>0.3). ROS1 alterations were significantly associated with metastatic breast cancer spread to the brain (p=0.0005) and lymph nodes (p=0.017). There were 18 gene mutations significantly co-occurring with ROS1 alterations when controlling for multiple comparisons. The top 5 were TP53 (OR 1.55, p=3.12 × 10−8), RB1 (OR 1.66, p=0.0001), NOTCH3 (2.27, p=0.0001), TAF1 (OR 4.82, p=0.0002), and ARID1A (OR 1.71, p=0.0003). Conclusions: A modest incidence of genomic alterations in ROS1 occurs across all breast cancer subtypes and histologies and may be more actionable than currently recognized. New somatic alterations in the ROS1 gene were identified from Foundation Medicine that were not detected in publicly available databases or Project GENIE. Investigations using PolyPhen2 and in vitro analyses of ROS1 gene activation from these newly discovered somatic alterations and other short variant mutations are currently being investigated in our lab with results to be reported. Co-occurring mutations reveal a unique genotype associated with ROS1 alterations that may play a biologic role in ROS1-mediated pathogenesis and should be explored further. ROS1 alterations occurring in breast cancers might be leveraged in an innovative personalized medicine treatment approach for breast cancer patients. Citation Format: Jeremy Force, Ethan S Sokol, Mary Love Taylor, Dale Huang, Paul K Marcom, Monika Davare, Jeffrey Marks. Incidence of ROS1 genomic alterations in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-09.

Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Introduction Identification of geriatric syndromes is important for determining functional age and optimizing care for people with cancer. Based on administration of a geriatric screening tool, we aimed to describe needed resources for geriatric syndromes, including lack of social support, depressed mood, deficits in instrumental and activities of daily living (IADL/ADL), falls, nutritional issues, polypharmacy, ability to pay for medications, and memory deficits, in a population of patients with breast cancer. Methods Consecutive medical oncology patients with breast cancer age 65 years and older, seen at a tertiary care center, completed a screening tool, adapted from Overcash 2006, consisting of a nurse-administered memory assessment and a one-page, self-administered questionnaire. Responses identified geriatric syndromes. Demographics and clinical information were retrospectively gathered. Frequencies and means were used to describe data. Results From January 2012 through July 2014, patients (n = 429) completed the screening tool as part of routine care. Study group had mean age 76 years (range 65–89), mean time since diagnosis 6.5 years, 91% non-metastatic disease, mean Charlson Comorbidity score 1.8 (range 0–10). Treatment included partial mastectomy (49%), adjuvant radiation (43%), chemotherapy (25%), and endocrine therapy (61%). The screening tool identified need for social support (8%); depression (31%); mobility issues (20%); falls (28%); nutritional needs (33%); polypharmacy (83%); and memory deficit (19%). Conclusion This screening tool identified geriatric syndromes requiring attention in many patients with breast cancer presenting for medical oncology appointments. In oncology practice, need for referral networks to address geriatric syndromes should be assessed.

The 2015 revision of the Worker Protection Standard (WPS) mandates requirements for medical evaluation, fit testing, and respirator training when the pesticide label requires a respirator. An ad-hoc group of Extension pesticide safety educators came together to address a lack of training and infrastructure for respirator compliance. In the ensuing years, programs of varied audiences and formats were hosted. Errors and shortcomings were realized, knowledge was gained, and lessons were learned. Those lessons are summarized here with links, resources, and suggestions for the implementation of similar efforts by Extension professionals.

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). The CTC-endocrine therapy index (CTC-ETI), consisting of CTC-ER (estrogen receptor), BCL2, human epidermal growth factor receptor (HER2), and Ki67 expression, might predict resistance to endocrine therapy (ET) in patients with ER-positive MBC. One hundred twenty-one patients with ER-positive/HER2-negative MBC initiating a new ET after ≥1 lines of ET were enrolled in a prospective, multi-institutional clinical trial. CTC-ETI and clinical/imaging follow-up were performed at baseline and serial time points. Progression-free survival (PFS) and rapid progression (RP; determined at the 3-month time point) were primary endpoints. Associations with clinical outcomes used logrank and Fisher’s exact tests. At baseline, 36% (38/107) of patients had ≥5 CTC/7.5 ml whole blood (WB). Patients with ≥5 vs. P = 0.03). Elevated CTC at 1 month was associated with even worse PFS (1.9 vs. 5.0 months from the 1-month sample, P P = 0.008). Patients with high vs. low CTC and CTC-ETI more frequently experienced RP (CTC: 66% vs. 41%; P = 0.03; CTC-ETI: 79% vs. 40%; P = 0.002). In conclusion, CTC enumeration and the CTC-ETI assay are prognostic at baseline and follow-up in patients with ER-positive/HER2-negative MBC starting new ET. CTC at first follow-up might identify a group of patients with ER-positive MBC that could forego ET, but CTC-ETI did not contribute further.

Objective The objective of this review is to determine the effectiveness of non-opioid pharmacological adjuncts for decreasing perioperative morphine equivalents and acute postoperative pain scores in adult surgical patients. Introduction Opioids are commonly administered during anesthesia to dull the senses, relieve pain and induce sleep. However, there are significant adverse effects associated with intraoperative opioid use. Anesthesia providers can impact the current opioid epidemic by administering non-opioid-centric anesthetic medications. A large-scale evidence-based review is needed to inform a standardized non-opioid pain treatment strategy in the perioperative period. Inclusion criteria This review will consider studies of adults 19 years or older who are undergoing surgical procedures and receiving non-opioid oral or intravenous perioperative analgesic medications administered by the anesthesia team. Studies that include patients who receive non-opioid medication as a local infiltrate by the surgical team will be excluded, as will studies with patients who receive regional or neuraxial opioid-sparing techniques. Only systematic reviews and meta-analyses published in English after 2007 will be considered. Methods MEDLINE, CINAHL and Embase will be searched, as well as two trial registers and two sources of unpublished reviews. Titles and abstracts will be screened to identify potentially relevant papers. Retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Meta-analyses will be performed if possible, and a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Summary of Findings presented. Systematic review registration number PROSPERO CRD42019135852.

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). Patients and Methods: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local–regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan–Meier method. Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4–96.2), and LRR-free survival was 98.6% (95% CI 97.4–99.8). LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Past studies indicate that90% of breast cancer survivors taking adjuvant endocrine therapy (AET) experience menopausal symptoms including sexual problems (eg, vaginal dryness, dyspareunia); however, research examining the impact of these problems on quality-of-life is limited. This cross-sectional study examined (1) the impact of sexual problems and self-efficacy for coping with sexual problems (sexual self-efficacy) on quality-of-life (ie, psychosocial quality-of-life and sexual satisfaction), and (2) partner status as a moderator of these relationships.Postmenopausal breast cancer survivors taking AET completed measures of sexual problems (Menopause-Specific Quality-of-Life [MENQOL] sexual subscale], sexual self-efficacy, psychosocial quality-of-life (MENQOL psychosocial subscale), and sexual satisfaction (Functional Assessment of Cancer Therapy-General item).Bivariate analyses showed that women reporting greater sexual problems and lower sexual self-efficacy had poorer quality-of-life and less sexual satisfaction (all P-values 0.05). Partner status moderated the relationship between sexual problems and psychosocial quality-of-life (P = 0.02); at high levels of sexual problems, unpartnered women experienced poorer psychosocial quality-of-life than partnered women. Partner status also moderated the relationship between self-efficacy and psychosocial quality-of-life (P = 0.01). Self-efficacy was unrelated to psychosocial quality-of-life for partnered women; for unpartnered women, low self-efficacy was associated with poorer quality-of-life. Partner status did not moderate the relationships between sexual problems or self-efficacy with sexual satisfaction.Greater sexual problems and lower sexual self-efficacy were associated with poorer psychosocial quality-of-life and sexual satisfaction among postmenopausal breast cancer survivors taking AET. Interventions to address sexual problems and sexual self-efficacy, particularly among unpartnered women, may be beneficial for improving the well-being of postmenopausal breast cancer survivors on AET.

Background Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics. Patients and methods The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out. Results Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. Conclusion Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome. Clinical trial registration clinicaltrials.gov identifier: NCT00542451.

Background: BRCA mutated (BRCA+) breast cancers are expected to have increased activation of Homologous Recombination Deficiency (HRD) and altered DNA damage repair pathways when compared to BRCA wildtype (BRCA-). To better understand differences in these populations, biological patterns and immune responses to BRCA+ breast cancers were evaluated. The primary aim of our study was to use novel gene expression tools to assess early stage breast cancers with and without germline BRCA mutations, and within distinct BRCA+ subgroups. Methods: We identified 124 early stage untreated breast cancers with and without BRCA mutations (n = 62 and 62, respectively). Our BRCA- group was matched by hormone receptor (HR) status, age, and stage to the BRCA+ group. The NanoString Breast Cancer 360 panel was applied to RNA isolated from 80 breast tumors (BRCA+ = 39; BRCA- = 41). The BRCA+ group had a BRCA1+ subgroup (n=17) and a BRCA2+ subgroup (n=22). Results: There was a significant increase in two BC360 signatures in both the BRCA1+ and BRCA2+ tumors compared with the BRCA- population: Prosigna™Risk of Recurrence (ROR) score [BRCA1+: HR: 1.142 (95% CI 1.019, 1.279), p=0.02; BRCA2+: HR: 1.321 (95% CI 1.190, 1.466), p Conclusions: In early stage BRCA+ breast cancer, tumors have higher ROR and increased HRD signature scores compared to BRCA- tumors. Furthermore, BRCA1+ and BRCA2+ tumors have both signature and single gene expression differences when compared to BRCA- tumors, indicating distinct subgroup-related biology. The greater correlation of BRCA1+ tumors with basal-like biology and BRCA2+ tumors with aggressive hormonal biology confirms these trends. Distinctions in hormone receptor signaling, DNA-damage pathways, and microenvironment/inflammatory features between BRCA1 and BRCA2 associated cancers suggest a need for different prevention and therapeutic strategies for each of these breast cancer subtypes. The unique biological patterns identified here should be further evaluated as predictive or prognostic tools that could be translated into clinical care for early stage BRCA+ patients. Citation Format: Force J, Plichta J, Stashko I, Kimmick G, Westbrook K, Sammons S, Hwang S, Hyslop T, Kauff N, Castellar E, Nair S, Weinhold K, Davis S, Mashadi-Hossein A, Brauer HA, Marcom PK. Distinct biological signatures describe differences in BRCA mutated subgroups [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-07.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Background While important in diagnosis of breast cancer, the scientific assessment of the role of imaging in prognosis of outcomes and treatment planning is limited. Purpose To evaluate the potential of using quantitative imaging variables for stratifying risk of distant recurrence in breast cancer patients. Study type Retrospective. Population In all, 892 female invasive breast cancer patients. Sequence Dynamic contrast-enhanced MRI with field strength 1.5 T and 3 T. Assessment Computer vision algorithms were applied to extract a comprehensive set of 529 imaging features quantifying size, shape, enhancement patterns, and heterogeneity of the tumors and the surrounding tissue. Using a development set with 446 cases, we selected 20 imaging features with high prognostic value. Statistical tests We evaluated the imaging features using an independent test set with 446 cases. The principal statistical measure was a concordance index between individual imaging features and patient distant recurrence-free survival (DRFS). Results The strongest association with DRFS that persisted after controlling for known prognostic clinical and pathology variables was found for signal enhancement ratio (SER) partial tumor volume (concordance index [C] = 0.768, 95% confidence interval [CI]: 0.679-0.856), tumor major axis length (C = 0.742, 95% CI: 0.650-0.834), kurtosis of the SER map within tumor (C = 0.640, 95% CI: 0.521-0.760), tumor cluster shade (C = 0.313, 95% CI: 0.216-0.410), and washin rate information measure of correlation (C = 0.702, 95% CI: 0.601-0.803). Data conclusion Quantitative assessment of breast cancer features seen in a routine breast MRI might be able to be used for assessment of risk of distant recurrence. Level of evidence 4 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019.

Pressures on North Carolina's agricultural community are at an unprecedented level. Known stressors are compounded by lawsuits, tariffs, and beliefs that others have a negative perception of agriculture. Individuals find themselves with an array of negative emotions precipitating stress, anxiety, depression, and increased risk of suicide without needed prevention.

Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1). Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6–12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis. Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23–53) among 18 who had received TH and 46 (range 34–54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045). Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.

North Carolina employs 78,000+ migrant/seasonal farmworkers (MSFWs) annually. Arrival/departure dates are crop and weather dependent. MSFWs may be employed by a grower or a farm labor contractor (FLC). Like farmworker housing, FLCs may be registered or unregistered. Primary care or enabling services are provided by the NC Farmworker Health Program or community health centers that receive dedicated federal funding for MSFWs. The arrival of NC's growing season, MSFWs, and COVID-19 brought unforeseen challenges even to those experienced in caring for MSFWs. Challenges include congregate activities, consistency/accuracy of COVID-19 related communications, availability of alternate housing, barriers to testing and contact tracing, lack of internet connectivity in farmworker housing and insufficient personal protective equipment. Challenges are discussed in no order of occurrence or level of importance as many are inter-related. To meet these challenges, a migrant health and housing workgroup was convened. Members include the NC Department of Labor-Agricultural Safety and Health Bureau, NC Department of Health and Human Services - Communicable Disease Branch and NC Farmworker Health Program, NC Community Health Center Association and NC Agromedicine Institute. Members work collaboratively along the continuum from local to state levels and across agencies and communities to facilitate strategies to address COVID-19 challenges. Implications exist for practice, research and policy including testing of MSFWs on arrival with a 14-day quarantine before moving to assigned farm, a "strike team" to do on-farm tests for workers in the event of a positive case or exposure; and, research on COVID-19 outbreaks and impact of telehealth on MSFWs wellbeing.

Background Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. Patients and methods This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I–III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. Results One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39–23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19–4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. Conclusions In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

Use of genomic assays to determine distant recurrence risk in patients with early stage breast cancer has expanded and is now included in the American Joint Committee on Cancer staging manual. Algorithmic alternatives using standard clinical and pathology information may provide equivalent benefit in settings where genomic tests, such as OncotypeDx, are unavailable. We developed an artificial neural network (ANN) model to nonlinearly estimate risk of distant cancer recurrence. In addition to clinical and pathological variables, we enhanced our model using intraoperatively determined global mammographic breast density (MBD) and local breast density (LBD). LBD was measured with optical spectral imaging capable of sensing regional concentrations of tissue constituents. A cohort of 56 ER+ patients with an OncotypeDx score was evaluated. We demonstrated that combining MBD/LBD measurements with clinical and pathological variables improves distant recurrence risk prediction accuracy, with high correlation (r = 0.98) to the OncotypeDx recurrence score. This article is protected by copyright. All rights reserved.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

PURPOSE Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) in germline (g) BRCA1/ 2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s) BRCA1/ 2 mutations or g/s mutations in homologous recombination (HR)–related genes other than BRCA1/2. METHODS Eligible patients had MBC with measurable disease and germline mutations in non- BRCA1/ 2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/ 2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS Fifty-four patients enrolled. Seventy-six percent had estrogen receptor–positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, s BRCA1/ 2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g PALB2 (ORR, 82%) and s BRCA1/ 2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g PALB2 and 6.3 months (90% CI, 4.4 months to NA) for s BRCA1/ 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION PARP inhibition is an effective treatment for patients with MBC and g PALB2 or s BRCA1/ 2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g BRCA1/ 2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

We report the results from a phase I study of buparlisib, an oral pan-class I phosphotidyinositol-3-kinase inhibitor, combined with capecitabine in patients with metastatic breast cancer. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m(2) twice daily. A complete response was seen in 1 patient with a basal-like tumor. Pharmacokinetic analysis suggested that a pharmacokinetic interaction might exist between the 2 agents. BACKGROUND: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m(2)) for 2 weeks with a 1-week break. Dose escalation used a traditional “3 + 3” design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose. RESULTS: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m(2) twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted. CONCLUSION: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug–drug interactions and more accurate predictive biomarkers of response.

PURPOSE: To define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS). METHODS: We collected data from 971 invasive breast cancers, from 1(st) January 2000 to 23(rd) March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease. RESULTS: Presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI: 2.22– 8.18, p

Key Points Question Can existing data sets be used to link sociodemographic, clinical, and genomic data into a single population-level data set to investigate disparities in cancer outcomes? Findings This cohort study used first-in-kind linkage of Surveillance, Epidemiology, and End Results, Medicare, and residual tumor repository data of 3522 women with newly diagnosed screening- vs symptomatic-detected estrogen receptor–positive nonmetastatic breast cancer to demonstrate that screening and socioeconomic factors remain associated with breast cancer outcomes, even after adjusting for clinical, demographic, and genomic factors. Meaning These findings suggest that screening detection, tumor stage, gene expression, and survival are associated phenomena that may offer novel insights when examined together within a single context., This cohort study uses linked registry data to investigate the biological and clinical progression of cancer associated with sociodemographic data and screening vs symptomatic detection in women with nonmetastatic invasive estrogen receptor–positive breast cancers., Importance Understanding interactions among health service, sociodemographic, clinical, and genomic factors in breast cancer disparities research has been limited by a disconnect between health services and basic biological approaches. Objective To describe the first linkage of Surveillance, Epidemiology, and End Results (SEER)–Medicare data to physical tumor samples and to investigate the interaction among screening detection, socioeconomic status, tumor stage, tumor biology, and breast cancer outcomes within a single context. Design, Setting, and Participants This population-based cohort study used tumor specimen blocks from a subset of women aged 66 to 75 years with newly diagnosed nonmetastatic, estrogen receptor–positive invasive breast cancer from January 1, 1993, to December 31, 2007. Specimens were obtained from the Iowa and Hawaii SEER Residual Tissue Repositories (RTRs) and linked with Medicare claims data and survival assessed through December 31, 2015. Data were analyzed from August 1, 2018, to July 25, 2021. Exposures Screening- vs symptom-based detection of tumors was assessed using validated claims-based algorithms. Demographic factors and zip code–based educational attainment and poverty socioeconomic characteristics were obtained via SEER. Main Outcomes and Measures Molecular subtyping and exploratory genomic analyses were completed using the NanoString Breast Cancer 360 gene expression panel containing the 50-gene signature classifier. Factors associated with overall and breast cancer–specific (BCS) survival were analyzed using Cox proportional hazards regression models combining sociodemographic, clinical, and genomic data. Results SEER-Medicare data were available for 3522 women (mean [SD] age, 70.9 [2.6] years; 3049 [86.6%] White), of whom 1555 (44.2%) were diagnosed by screening mammogram. In the SEER-Medicare cohort, factors associated with increased BCS mortality included symptomatic detection (hazard ratio [HR], 1.49 [95% CI, 1.16-1.91]), advanced disease stage (HR for stage III, 2.33 [95% CI, 1.41-3.85]), and high-grade disease (HR, 1.85 [95% CI, 1.46-2.34]). The molecular cohort of 130 cases with luminal A/B cancer further revealed increased all-cause mortality associated with genomic upregulation of transforming growth factor β activation and p53 dysregulation (eg, p53 dysregulation: HR, 2.15 [95% CI, 1.20-3.86]) and decreased mortality associated with androgen receptor, macrophage, cytotoxicity, and Treg signaling (eg, androgen receptor signaling: HR, 0.23 [95% CI, 0.12-0.45]). Symptomatic detection (HR, 2.49 [95% CI, 1.19-5.20]) and zip codes with low levels of educational attainment (HR, 5.17 [95% CI, 2.12-12.60]) remained associated with mortality after adjusting for all clinical and demographic factors. Conclusions and Relevance Linkage of SEER-Medicare data to physical tumor specimens may elucidate associations among biology, health care access, and disparities in breast cancer outcomes. The findings of this study suggest that screening detection and socioeconomic status are associated with survival in patients with locally advanced, estrogen receptor–positive tumors, even after incorporating clinical and genomic factors.

Pre-clinical and clinical data suggest that the bone marrow (BM) environment provides breast cancer (BC) cells a protective haven against chemotherapeutic insult, endocrine therapies, and immune recognition. Novel agents that intercept cross-talk between BC cells and the host could therefore improve the depth of response to therapies and potentially increase overall survival in metastatic BC. We have previously shown that bone metastatic BC cells reside in perivascular niches expressing high levels of SDF-1α (CXCL12) and E-selectin, two molecules for which emerging data have demonstrated a significant role in metastatic BC progression. Our prior pre-clinical studies have shown that E-selectin inhibition specifically prevents circulating BC cells from homing to the BM, whereas CXCR4 blockade mobilizes micrometastases from the marrow into circulation, where they may be sensitized to chemotherapeutic cell kill. Given the normal role of these molecules in host immune responses, E-selectin/CXCR4 blockade has additional potential to impact the tumor immune microenvironment. GMI-1359 is a small molecule, glycomimetic compound with dual inhibitory activity against E-selectin and CXCR4. We hypothesize that GMI-1359 can block E-selectin and CXCR4 binding to E-selectin ligands and SDF-1, disrupting the protective effects of the bone microenvironment on tumor cells. A single-center, phase 1b, open-label, single and multiple ascending dose study (NCT04197999) is therefore evaluating GMI-1359 in patients with HR+ metastatic breast cancer with bony metastases who are stable or minimally progressive on endocrine therapy, with or without a CDK4/6 inhibitor. To date, 2 patients have been enrolled and received single monthly doses of 3.5, 5.0 and 7.0 mg/kg followed by 3 daily doses of 7 mg/kg. Both patients have completed treatment with no dose limiting toxicities observed. Coincident with GMI-1359 administration at all dose levels, we observed mobilization of CD34+ cells coupled with a reduction in elevated serum sE-selectin levels, demonstrating the dual functionality of the compound. Initial peripheral blood immunophenotype data on one patient revealed a redistribution of myeloid derived suppressor cells and a shift in macrophage polarization from M2 to M1. Notably, we observed similar immune alterations in ongoing preclinical studies in the E0771 syngeneic BC mouse model. We found that orthotopically-engrafted mice treated with single agent 1359 had a significant increase in the ratio of CD8/Tregulatory cells isolated from the primary tumor and BM. We also observed a decrease in primary tumor M-MDSCs and lung metastasis-associated macrophages. In summary, our preliminary clinical data suggest that GMI-1359 is well-tolerated and elicits on-target effects expected from disruption of the host microenvironment. Ongoing clinical and preclinical work will define the efficacy of this strategy to enhance responses to chemo and immune therapies. Citation Format: P. Kelly Marcom, Trevor T. Price, Andrew S. Murray, William E. Fogler, John L. Magnani, Helen Thackray, Eric Feldman, Dorothy Sipkins. Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT144.

Introduction: The irreversible pan-HER inhibitor NER showed modest single agent activity for HER2mut MBC in Part I of MutHER trial. In Part II, we hypothesized that (1) N+F would improve activity in estrogen receptor positive (ER+) HER2mut MBC due to ER-HER2 crosstalk and (2) dual HER2 blockade by adding trastuzumab at disease progression (PD) could overcome resistance. Methods: Pts with ER+HER2mut MBC were enrolled to 2 cohorts (FUL treated or naive) to receive N+F with diarrhea prophylaxis. ER- pts received NER in an exploratory ER- cohort. Trastuzumab was added at PD if approved by insurance. Simon's Minimax 2-stage phase II design with the primary endpoint of clinical benefit rate (CBR: rates of complete/partial response [CR/PR] plus stable disease [SD] >24 weeks [wks]), with anticipated vs null hypothesis being CBR of 55% vs 35% (FUL treated) or 65% vs 40% (FUL naïve) with 80% power, 1 sided 0.05 alpha, was used. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Serial blood samples were analyzed for circulating tumor DNA (ctDNA) by Guardant360 for concomitant mutations, HER2mut variant allele frequency (VAF) dynamics, and resistance mechanisms. Results: Between Sep. 2015 and Oct. 2020, 40 pts with HER2mut MBC were enrolled, completing the 1st stage of each ER+ cohort. 35 pts (21 FUL treated, 10 FUL naïve, 4 ER-) were evaluable for response, with median age 63 (35-82) years, 3 (0-12) prior MBC regimen, lobular BC in 13 (37%) and visceral mets in 32 (91%) pts. 21 (68%) ER+ pts had prior CDK4/6 inhibitor. All but 1 pt has come off study due to PD. Table 1 shows the efficacy by cohort. Further enrollment is closed per protocol. Adding trastuzumab at PD induced CB in 4 (3 PR, 1 SD≥24 wks) of 5 pts (1 ER-, 4 ER+), with PFS 28 (95% CI 18~NA) wks. Common AEs across cohorts were diarrhea (G3 21%) and fatigue (G3 5%). No G4 AEs. ctDNA HER2mut was detected in 72% (23/32) baseline (BL) samples tested. In pts with paired samples, HER2mut VAF decreased at C1D15/C2D1 from BL in 75% (15/20) and rose in 89% (16/18) at PD. Acquired HER2mut, including the T798I gatekeeper mutation, were detected in 2 pts at PD. Mutations in TP53 (53%), PIK3CA (43%), and CDH1 (35%) were common, but none significantly associated with PFS in all or ER+ pts. Conclusions: NER, or N+F, is active for HER2mut MBC with good tolerability. Adding trastuzumab at PD induced further response, supporting dual HER2 blockade for HER2mut MBC. Table 1.EfficacyCohortFUL treatedFUL naïveER-Best Response, n evaluablen = 21n = 10n = 4CR, n100PR, n431SD (≥ 24 wks), n300SD (< 24 wks), n1030PD, n343CBR, n with CB/total n evaluable, % (95% CI)8 of 20*, 40% (19~64%)3 of 10, 30% (7~65%)1 of 4, 25% (0.6~81%)mPFS (95% CI), wks, ITT (n)24 (16~31) wks, (n = 24)20 (8~NA) wks, (n = 11)8.5 (8~NA) wks, (n = 5)*20 of 21 pts are evaluable for CBR in the FUL treated Cohort as 1 pt had SD as best response and treatment is still ongoing. ITT (intent to treat) population is used for mPFS estimate. Citation Format: Cynthia X. Ma, Jingqin Luo, Rachel A. Freedman, Timothy Pluard, Julie Nangia, Janice Lu, Frances Valdez-Albini, Melody Cobleigh, Jason Jones, Nancy U. Lin, Eric Winer, P. Kelly Marcom, Shana Thomas, Jill Anderson, Brittney Haas, Kimberly M. Hamann, Richard Bryce, Alshad S. Lalani, Lisa Carey, Matthew Goetz, Feng Gao, Gretchen Kimmick, Mark Pegram, Matthew J. Ellis, Ron Bose. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT026.

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA+ per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2-mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Table 1Efficacy (ITT population – BRCA mutation)Plc+C/P, n=98V+C/P, n=95HR (95% CI); P valuePFS(mo, 95% CI)12.3 (9.3–14.5)14.1 (11.5–16.2)0.789 (0.536–1.162); 0.231OS (mo, 95% CI)25.0 (18.1–34.8)28.5 (22.4–NR)0.725 (0.468–1.121); 0.148ORR, % (95% CI)61.3 (49.7–71.9)77.8 (66.4–86.7)P=0.027 Citation Format: Han HS, Diéras V, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-05.

Given the potential savings in cost and resource utilization, several algorithms have been proposed to predict Oncotype DX recurrence score (ODX RS) using commonly acquired histopathologic variables. Although it is promising, additional independent validation of these surrogate markers is needed prior to guide the patient management.In this retrospective study, we analyzed 305 patients with invasive breast cancer at our institution who had ODX RS available. We selected five equations that provide a surrogate measure of ODX as previously published by Klein et al. (Magee equations 1-3), Gage et al., and Tang et al. All equations used estrogen receptor status and progesterone receptor status along with different combinations of grade, proliferation indices (Ki-67, mitotic rate), HER2 status, and tumor size.Of all surrogate scores tested, the Magee equation 2 provided the highest correlation with ODX both with regard to raw score (Pearson's correlation coefficient = 0.66 95% CI 0.59-0.72) and categorical correlation (Cohen's kappa = 0.43, 95% CI 0.33-0.53). Although Magee equation 2 provided a way to reliably identify high-risk disease by assigning 95% of the patients with high ODX RS to either the intermediate- or high-risk group, it was unable to reliably identify the potential for patients to have intermediate- or high-risk disease by ODX (66% of such patients identified).Although commonly available surrogates for ODX appear to predict high-risk ODX RS, they are unable to reliably rule out the presence of patients with intermediate-risk disease by ODX. Given the potential benefit of adjuvant chemotherapy in women with intermediate-risk disease by ODX, current surrogates are unable to safely substitute for ODX. Characterizing the true recurrence risk in patients with intermediate-risk disease by ODX is critical to the clinical adoption of current surrogate markers and is an area of ongoing clinical trials.

PURPOSE The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)–positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN). PATIENTS AND METHODS In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer–specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN. RESULTS A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%). CONCLUSION With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.

BACKGROUND The National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) uses a 10-point scale (in which 0 indicates no distress and 10 indicates extreme distress) to measure patient-reported distress. In the current study, the authors sought to examine the relationship between treatment and NCCN DT scores in patients with breast cancer over time. METHODS The authors included women aged ≥18 years who were diagnosed with stage 0 to stage IV breast cancer (according to the seventh edition of the American Joint Commission on Cancer staging system) at a 3-hospital health system from January 2014 to July 2016. Linear mixed effects models adjusted for covariates including stage of disease, race/ethnicity, insurance, and treatment sequence (neoadjuvant vs adjuvant) were used to estimate adjusted mean changes in the DT score (MSCs) per week for patients undergoing lumpectomy, mastectomy only, and mastectomy with reconstruction (MR). RESULTS The authors analyzed 12,569 encounters for 1029 unique patients (median score, 4; median follow-up, 67 weeks). Patients treated with MR (118 patients) were younger and more likely to be married, white, and privately insured compared with patients undergoing lumpectomy (620 patients) and mastectomy only (291 patients) (all P

OBJECTIVE: To explore the impact of symptoms on physical function in women on adjuvant endocrine therapy for breast cancer. METHODS: Eligible women were postmenopausal, had hormone receptor positive, stage I-IIIA breast cancer, completed surgery, chemotherapy, radiation, and on adjuvant endocrine therapy. At a routine follow-up visit, women (N=107) completed standardized symptom measures: Brief Fatigue Inventory, Brief Pain Inventory, Menopause Specific Quality of Life Questionnaire, Functional Assessment of Cancer Therapy Neurotoxicity scales. Two performance measures assessed function: grip strength (Jamar dynamometer; n=71) and timed get-up-and-go (TUG; n=103). Analyses were performed with an overall symptom composite score. Correlations and multiple linear regression analyses were performed to test adverse effects on physical function. RESULTS: The mean age was 64 years (range 45–84), 81% white, 84% on an aromatase inhibitor, and on endocrine therapy for mean 35 months (range 1–130 months). Dominant hand grip strength was inversely correlated with symptom composite scores (r=−.29, p=.02). Slower TUG was positively correlated with higher Charlson comorbidity level (r=.36, p

Certified Safe Farm (CSF) is a multimodal safety and health program developed and assessed through multiple controlled intervention studies in Iowa. Although developed with the intent to be broadly applicable to agriculture, CSF has not been widely implemented outside the midwestern United States. This article describes the CSF implementation process in North Carolina (NC), as piloted on a large-scale in three agriculturally diverse and productive counties of NC, and reports its effectiveness using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. Implementation involved (1) capacity building through safety and health training, (2) adaptation of components of Iowa's CSF model to NC agriculture, (3) marketing and recruitment, and (4) formative evaluation, including an online survey and focus group discussion. From 2009 to 2012, 113 farms participated in at least one component of the CSF intervention, representing a NC farm participation rate of 3.1% in the study area. A major adaptation of NC implementation was the utilization of NC Cooperative Extension as the local driver of implementation in contrast to local AgriSafe clinics in Iowa. The most innovative adaptation to CSF components was the development of a defined economic incentive in the form of a cost-share program. The RE-AIM framework was found to be useful and relevant to the field of agricultural health and safety translational research. This study provides effectiveness measures and implementation alternatives useful for those considering implementing CSF. It informs current efforts to move CSF from research to practice through the National Sustainable Model CSF Program initiative.

Purpose The purpose of this study is to investigate the association between breast cancer recurrence-free survival and breast magnetic resonance imaging (MRI) tumor enhancement dynamics which are quantified semi-automatically using computer algorithms. Methods In this retrospective IRB-approved study, we analyzed data from 275 breast cancer patients at a single institution. Recurrence-free survival data were obtained from the medical record. Routine clinical pre-operative breast MRIs were performed in all patients. The tumors were marked on the MRIs by fellowship-trained breast radiologists. A previously developed computer algorithm was applied to the marked tumors to quantify the enhancement dynamics relative to the automatically assessed background parenchymal enhancement. To establish whether the contrast enhancement feature quantified by the algorithm was associated with recurrence-free survival, we constructed a Cox proportional hazards regression model with the computer-extracted feature as a covariate. We controlled for tumor grade and size (major axis length), patient age, patient race/ethnicity, and menopausal status. Results The analysis showed that the semi-automatically obtained feature quantifying MRI tumor enhancement dynamics was independently predictive of recurrence-free survival ( p = 0.024). Conclusion Semi-automatically quantified tumor enhancement dynamics on MRI are predictive of recurrence-free survival in breast cancer patients.

Background: Increased stromal tumor infiltrating lymphocytes (TILs) are predictive and prognostic for improved outcomes from neoadjuvant or adjuvant chemotherapy in triple negative breast cancer. Increased tumor mutational burden may promote neoantigens causing immune system upregulation. Microsatellite instability in gastrointestinal cancer predicts for response to checkpoint inhibition and is associated with inherited cancer predisposition. The immune system response in BRCA mutated breast cancer has not been described. The purpose of this study is to assess tumor infiltrating immune cells in early stage breast cancer patients with and without BRCA gene mutations. Methods: We retrospectively investigated 124 early stage breast cancer patients with BRCA mutations (n=62, BRCA+) and without BRCA mutations (n=62, BRCA WT). The %TILs was measured manually by H&E. Our control group consisted of age, stage, and receptor status matched early stage untreated breast cancer patients who were deemed BRCA WT by extended gene panel testing or were negative for BRCA 1/2 and had a posttest probability of harboring an autosomal dominant mutated gene of ≤ 1% using the Bayes-Mendel algorithm. We used a two-sample binomial arcsin approximation to detect a 20% difference in TILs between cohorts to attain 80% power with a one-side alpha of 0.05. Wilcoxon Rank-Sums test was used to compare differences in the central tendencies for continuous variables. We used the Nanostring PanCancer immune profiling panel to immunophenotype a portion of the BRCA+ and BRCA WT cohorts and used nSolver for quality control, normalization, and bioinformatics analyses. Results: Here we report TILs from the first 21 patients of our study. Thirteen patients harbored BRCA mutations and eight patients did not. All patients were HER2 negative. Eight (61%) and four (50%) patients were hormone receptor positive (HR+) in the BRCA+ and BRCA WT cohorts, respectively. Median %TILs were not significantly different between the BRCA+ (15, range 0-70) and BRCA WT (17.5, range 5-60; p=0.7) groups. Median %TILs in the HR+/BRCA+ (12.5, range 0-50) and HR-/BRCA+ (15, range 5-70) cohorts were not statistically different when compared to HR+/BRCA WT (10, range 5-15; p=0.4) and HR-/BRCA WT (30, range 20-60; p=0.2) cohorts, respectively. There were 2 patients with lymphocyte predominant breast cancer (n=1, HR-/BRCA+; n=1, HR-/BRCA WT). Conclusions: This is the first study to characterize TILs and a tumor immune microenvironment phenotype in early stage breast cancer patients with BRCA mutations. These results suggest harboring a BRCA mutation is not associated with increased TILs in early stage untreated breast cancer patients. This conclusion stayed true regardless of hormone receptor status. However, a trend of decreased TILs was seen in HR-/BRCA+ patients when compared to those with HR-/BRCA WT disease. Moreover, the median and range of TILs were higher in the HR+/BRCA+ group compared to the HR+/BRCA WT group. This suggests increased TILs may exist in some HR+ patients with a BRCA mutation. Further investigation of TILs and immune profiling of early stage untreated breast cancer patients with and without BRCA mutations is warranted. Citation Format: Force J, Abbott S, Broadwater G, Kimmick G, Westbrook K, Hwang S, Kauff N, Stashko I, Weinhold K, Nair S, Hyslop T, Blackwell K, Castellar E, Marcom PK. Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-19.

e13017 Background: HER2-directed therapies enable a small number of patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long term durable responses (DR). However, clinic-pathologic factors that correlate with DRs in de novo HER2+ MBC are unknown. Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice, especially the effect on cardiotoxicity, are lacking in the literature. Methods: This is a retrospective case control study of patients with de novo HER2+ MBC who received treatment with trastuzumab at two NCI designated cancer centers between the years 2012-2017. Patients were included if ≥2 years of follow up data were available or if patients were deceased. DRs are defined as radiographic complete or partial response without progression or death at any point after diagnosis. Controls are patients with evidence of radiographic progression or death any point after diagnosis. Age at diagnosis, ER/PR status, site of metastasis, and initial treatment were analyzed. An un-paired T test for age and fisher exact test for categorical variables were used. Results: A total of 96 patients with de novo HER2+ MBC, 28 with DRs and 68 with progression, were identified. Average follow up length for patients with DR was 90 months (range 27-224 months). Patients who progressed had a mPFS of 17.5 months and a mOS of 60 months. Results are shown in Table. Additionally, six patients (6.3%) developed reduced ejection fraction, one with DR, five with progression. Nine patients have been receiving trastuzumab for over ten years with no evidence of disease. Only one patient opted to discontinue this therapy a year after complete response and is disease free five years from diagnosis. Conclusions: Nearly a third of patients with de novo metastatic HER2+ MBC in our dataset achieved DR. Factors that predict DRs include single organ involved by metastatic disease and more intensive upfront chemotherapy including trastuzumab and pertuzumab. The majority of patients with DR continued HER2 directed therapy indefinitely with minimal cardiotoxicity. In the absence of predictive biomarkers of DRs, indefinite trastuzumab administration is common practice for these patients. [Table: see text]

1516 Background: The proportion of germline versus somatic mutations identified on genomic tumor testing of solid malignancies is not well characterized. We compared somatic and germline testing results in patients with breast, ovarian, pancreatic or prostate cancer with a genomic alteration identified on tumor testing. Methods: Retrospective chart review was performed using a tertiary care academic center’s database of somatic tumor testing results obtained via FoundationOne and Guardant testing. Patients with breast, ovarian, pancreatic or prostate cancer who had a genomic alteration identified on tumor testing, including pathogenic and VUS variants, in BRCA1or BRCA2, CHEK2, ATM, BRIP1, RAD51C, RAD51D, PALB2and CDH1and who had also received germline testing were identified. Analysis was performed to assess prevalence of germline results. The association between mutant allele fraction (MAF) and germline mutation status was also assessed. Results: Results: 124 patients with breast, ovarian, pancreatic or prostate cancer were identified who had a genomic alteration of interest also tested for via germline testing. 54 (32.5%) of tumor mutations were also identified on germline testing. Proportion of genomic results that were germline was wide, ranging from 0-85.7% depending on the gene and variant classification (Table). Germline mutations were present in 36.4% of breast, 25% of ovarian, 53.3% of pancreatic, and 20.9% of prostate cancer patients who had a tumor alteration present. Alterations that were found to be concordant in both somatic and germline testing had an average MAF of 0.54, and alterations identified on somatic testing only had an average MAF of 0.30. Conclusions: Our findings suggest that approximately one-third of genomic alterations on tumor testing will be of germline origin. However, concordance rates may be gene and variant dependent. Higher MAF may be associated with germline alteration status, but further evaluation is needed. Thus, while information provided by genomic tumor testing may be suggestive of a correlating germline mutation, no single alteration type or MAF value is reliably predictive. [Table: see text]

1031 Background: ROS1 is an important proto-oncogene involved in the development of various cancers for which we have FDA approved therapies. While activation of the ROS1 tyrosine kinase receptor has been reported in 1-2% of lung cancers, the frequency and type of ROS1 alterations in breast cancer have not been fully explored. We previously described the incidence of ROS1 alterations from breast cancer tissue. The purpose of this study was to identify the incidence of ROS1 genomic alterations occurring in cfDNA from patients with breast cancer. Methods: We queried 16,053 breast cancer samples from the Guardant Health breast cancer database between June 2015 - October 2019 to identify the incidence of ROS1 alterations detected in cfDNA in breast cancer. We identified fusion partner genes and classified each alteration type into the following categories: fusion, single nucleotide variants (SNVs), and indels. Radical amino acid changes occurring at conserved regions across the ROS1 gene were identified. In vitro analyses were used to investigate the effect of ROS1 nonsynonymous mutations on the ROS1 protein. We made associations with ROS1 alterations and co-occurring mutated genes. Results: Nonsynonymous ROS1 alterations from the Guardant Health breast cancer database were found in 162 samples from 142 patients in the 16,053-patient cohort (1%). Alterations found included: 1 (0.6%) ROS1-SLC35F1 fusion, 155 (95.7%) SNVs, and 6 (3.7%) indels. Of the 155 SNVs, we identified 23 (14.8%) mutations occurring in the ROS1 kinase, of which, 20 (12.9%) occurred at highly conserved regions and 15 (9.6%) harbored radical amino acid changes. The top 5 co-occurring mutations in samples with ROS1 alterations were TP53 (50%), PIK3CA (44%), ESR1 (27%), EGFR (21%), and FGFR1 (18%). Conclusions: A modest incidence of ROS1 genomic alterations occurs in cfDNA from patients with breast cancer. New somatic alterations in the ROS1 gene were identified from Guardant Health that were not detected in publicly available databases. A portion of mutations occurred at highly conserved regions across the ROS1 gene suggesting these may be more actionable than currently recognized. In vitro analyses of ROS1 gene activation from these newly discovered somatic alterations are being investigated with results to be reported. Co-occurring mutations reveal a unique genotype associated with ROS1 alterations that may play a biologic role in ROS1-mediated pathogenesis.

1002 Background: Olaparib, a PARP inhibitor, is approved for HER2-negative MBC in g BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated study, assessed the response to olaparib in MBC patients with sBRCA1/2 mutations or g/s mutations in DDR-pathway genes other than BRCA1/2. Methods: Eligibility included: MBC with measurable disease; progression on < 2 metastatic chemotherapy regimens. Prior PARP inhibitor or progression on platinum was not allowed. Cohort 1 included patients with germline mutations in non- BRCA1/2 DDR-pathway genes. In Cohort 2 were those with somatic mutations in these genes or BRCA1/2; germline testing was required only to exclude a gBRCA mutation if a s BRCA mutation was present. Patients received olaparib 300 mg bid until progression or unacceptable toxicity. For each cohort, a single-arm Simon two-stage design was used with 13 then 14 patients in the 1st and 2nd stages, respectively. The null hypothesis within each cohort [≤ 5% objective response rate (ORR)] would be rejected if > 4 responses were seen at the end of stage 2. Secondary endpoints include clinical benefit rate, progression-free survival, and duration of response. Results: 54 patients enrolled from March 2018 to Jan 2020; 1 ineligible s BRCA2 was excluded. Median age was 59 yrs (range: 30-87). 40 patients had ER+ HER2-, 3 HER2+, and 10 TNBC. 87% had a mutation in PALB2, s BRCA1/2, ATM or CHEK2. ORR was 29.6% (8/27, 90%-CI: 15.6%-47.1%) in Cohort 1 and 38.5% (10/26, 90%-CI: 22.5%-56.4%) in Cohort 2. Responses were gene specific (Table): g PALB2 and s BRCA mutations predicted response; no responses were seen with only a CHEK2 or ATM mutation. To date, responses as long as 16.4 months have been observed. Responses were seen in all subtypes: 5/10 TNBC, 1/3 HER2+, 12/40 ER+ HER2-. 11 responses occurred after prior CDK4/6 inhibitor. In June 2020, final data for confirmed ORR and secondary endpoints will be reported. Conclusion: In this proof-of-principle study, single-agent olaparib successfully met its primary endpoint in both cohorts. Activity was seen largely in patients with MBC and s BRCA1/2 or g PALB2 mutations but not with ATM or CHEK2 mutations. Clinical trial information: NCT03344965 . [Table: see text]

Background: Single-agent platinum compounds have significant clinical activity in the neoadjuvant and metastatic settings for triple-negative breast cancer (TNBC) in BRCA mutation carriers. Limited data exist regarding activity in estrogen receptor (ER)-positive breast cancer among BRCA carriers. The INFORM trial is an investigator-initiated, randomized, multicenter, phase II study comparing pathologic complete response (pCR) rates with neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin/cyclophosphamide (AC) in BRCA carriers with newly-diagnosed Stage I-III HER2-negative breast cancer. Methods: BRCA carriers with cT1-3 (≥1.5 cm), cN0-3 HER2-negative breast cancer were randomized (stratified by site and ER status) 1:1 to preoperative CDDP (75mg/m2 every 3 wks x 4) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 wks x 4) followed by surgery. Prior chemotherapy was not allowed; subsequent adjuvant therapy was selected by treating clinicians. Baseline tumor features and pathologic responses were centrally determined. The primary endpoint was pCR (ypT0/is, N0). Based on a 2-sided α=0.1, a sample size of 170 provided 80% power to detect an improvement in pCR from 30% with AC to 50% with CDDP. Slow accrual led to early trial closure. We used an intent-to-treat approach and log-binomial regression to calculate risk ratios (95% confidence intervals (CI)), adjusting for ER status. Results: We randomized 118 patients; 117 were included in outcome analyses. The mean age was 42 years (range: 24-73); 69% were BRCA1+, 30% BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% of patients had nodal involvement at baseline. Most patients (70%) had TNBC (ER/PR Table 1: Intention-to-treat analysis comparing CDDP to ACCDDP n=60 n (%)AC* n=57 n (%)Crude Risk Ratio (95% CI)Adjusted Risk Ratio§ (95% CI)Pathologic complete responseResidual cancer burden score: 0All participants11 (18)15 (26)0.70 (0.35-1.4)0.67 (0.35-1.3)Triple negative (ER and PR Conclusion: While CDDP has single-agent activity in BRCA carriers with HER2-negative breast cancer, the pCR rate with CDDP is not higher than with standard AC chemotherapy. CDDP activity was notably lower in BRCA carriers with hormone-receptor positive breast cancer, though the sample size was small. Study-collected tumor and blood samples are being analyzed for biomarkers of response. Clinical information: NCT01670500. Funding: Breast Cancer Research Foundation; Susan G. Komen for the Cure; Myriad Genetics, Inc. Citation Format: Nadine Tung, Banu Arun, Erin Hofstatter, Michele R. Hacker, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul K. Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber. Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-03.

PURPOSE: To determine whether a multivariate machine learning-based model using computer-extracted features of pre-treatment dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can predict pathologic complete response (pCR) to neoadjuvant therapy (NAT) in breast cancer patients. METHODS: Institutional review board approval was obtained for this retrospective study of 288 breast cancer patients at our institution who received NAT and had a pre-treatment breast MRI. A comprehensive set of 529 radiomic features was extracted from each patient’s pretreatment MRI. The patients were divided into equal groups to form a training set and an independent test set. Two multivariate machine learning models (logistic regression and a support vector machine) based on imaging features were trained to predict pCR in (a) all patients with NAT, (b) patients with neoadjuvant chemotherapy (NACT), and (c) triple negative or human epidermal growth factor receptor 2-positive (TN/HER2+) patients who had NAT. The multivariate models were tested using the independent test set, and the area under the receiver operating characteristics (ROC) curve (AUC) was calculated. RESULTS: Out of the 288 patients, 64 achieved pCR. The AUC values for predicting pCR in TN/HER+ patients who received NAT were significant (.707, 95%CI: 0.582–0.833, p < 0.002). CONCLUSIONS: The multivariate models based on pre-treatment MRI features were able to predict pCR in TN/HER2+ patients.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.