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Introduction: Given excellent survival outcomes in breast cancer and new methods to predict treatment response, oncologists are interested in de-escalating the amount of chemotherapy delivered to patients. This is particularly important in the setting of COVID-19, where patient perspectives of de-escalation may be altered by perception of COVID-19 risk.Methods: This concurrent mixed methods study included (1) semi-structured interview data from patients with breast cancer treated at the University of Alabama at Birmingham and patient advocates from nationally representative advocacy organizations (10/2019-5/2020) and (2) cross-sectional survey data from a nationwide sample of women with breast cancer (11/19-12/2019). Questions evaluated interest in de-escalation study participation, perceived barriers/facilitators to participation, and language describing de-escalation. Participant perspectives surrounding COVID-19 impact on de-escalation were elicited in interviews post 3/2020.Results: Quantitative and qualitative findings were synergistic. Interviews were conducted with 40 female participants (24 patients, 16 patient advocates). Participant ages ranged from 33-79 years old; 30% were minorities; 35% didn’t have a college degree. Common barriers to acceptance of de-escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for the focus on less treatment. Fear of recurrence was the most commonly expressed barrier, with one participant stating, “I’m just afraid it wouldn’t get it all”. Common facilitators included trust in the physician, toxicity avoidance, monitoring with the option of increasing treatment intensity, perception of good prognosis, and impact on daily life. Participants interviewed during the COVID-19 pandemic (n=16) expressed substantial virus-related fear, including fear of exposure, fear of infecting their personal contacts or health care team, fear of cancer-related complications, and fear about their immunocompromised state. These fears contributed to participants perspective on de-escalation, as highlighted by participants stating, “I wouldn't worry about getting the chemo as much as I would worry about getting the virus” and “Less is more for me right now”.Of 91 survey respondents (69% response rate), median age was 58 years (interquartile range [IQR] 48-69), 86% had early stage breast cancer. Many (43%) patients were not interested in participation in a study testing lower doses of chemotherapy than standard of care. Patients not interested in participating were more often unmarried (55% vs. 32%, V=.23), disabled (56% vs. 40%, V=.17), or diagnosed with early stage cancer (45% vs. 22%, V=.14). Barriers to participation included fear of cancer recurrence (85%) and regret about the decision to receive less chemotherapy if the cancer were to recur (79%). Few patients (19%) considered clinical trials themselves as a barrier. Patients were interested in participation due to lessened physical side effects of treatment (82%), lessened long-term problems related to treatment (76%), and lessened impact on daily life (72%). The most popular terminology describing chemotherapy de-escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de-escalation.” Conclusion: Fear of recurrence is a common barrier to de-escalation clinical trial participation in patients with breast cancer. Fears may be altered for patients considering treatment during the COVID-19 pandemic. Trust in the physician and use of patient-generated language, such as “customized” instead of “de-escalation”, are potential areas for future interventions engaging patients in trials. Citation Format: Gabrielle Rocque, Courtney P. Williams, Courtney J. Andrews, Kathleen Gallagher, Timothy C. Childers, Kimberly D. Wiseman, Alan Balch, Stacey A. Ingram, Thelma Brown, Tara Kaufman, Nadine Tung, Mary Lou Smith, Antonio C. Wolff, Angela DeMichele, Lynn Wagner. Patient perspectives on chemotherapy de-escalation: “Don’t de-escalate! I don’t want to die!” [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 PD3-10.

Background: Despite known benefits in reducing breast cancer (BC) recurrence and death, up to 50% of patients discontinue endocrine therapy (ET) early. Symptoms are often cited as a reason for early ET discontinuation (DC). The symptom burden during ET captured by patient reported outcomes (PRO) exceeds that captured by clinicians. Methods: We initiated a single arm pilot trial evaluating symptom monitoring during ET with PRO collected via smart phone app. Eligible patients are women starting ET for stage 0-III BC. Participants receive text message reminders to complete surveys at baseline (BL), 1, 3, 6 and 12 months (mo). Participants who do not complete 2 sequential surveys may opt out of further surveys. Surveys include PROMIS measures for anxiety, depression, fatigue and the vaginal discomfort domain of sexual function plus PRO-CTCAE measures for concentration, memory, hot flashes, joint pain and vaginal dryness. PROMIS measures are scored by T-score look up tables. PRO-CTCAE responses are reported on a 5 point scale (0-4). Severe or worsening scores trigger email alerts to clinicians as follows: T-scores ≥70 or ≥5 points worse than BL for anxiety, depression, and fatigue; T-score ≥65 or ≥5 points worse than BL for sexual function; scores ≥3 or ≥2 points worse than BL on PRO-CTCAE measures. Recommended management pathways are provided to clinicians upon alert acknowledgement. The primary endpoint is feasibility, with success defined as ≥65% of participants completing the BL survey and ≥65% of participants completing ≥1 follow-up (FU) survey during the first 6 mo of ET. Secondary endpoints include patient-reported symptoms and pathway-concordant symptom management based on chart review. We report here descriptive statistics of the observed data to date and multivariate logistic regression analysis of factors associated with BL survey completion. Results: From Feb 2019 to May 2020, 213 of 250 planned participants enrolled. Median FU is 5.7 mo. Mean age is 58.3 years (SD 11.7). 154 (72.3%) participants are white (W) and 32 (15%) are black (B). 189 (88.7%) participants have stage I-II BC. Prior to initiating ET, 82 (39%) had mastectomy, 75 (35.2%) had chemotherapy and 135 (63.4%) had radiation. 138 (64.8%) initiated an aromatase inhibitor and 72 (33.8%) initiated tamoxifen. BL survey completion rate is 73.7% (95% confidence interval (CI) 67.3-79.5%). To date, 69.3% (95% CI 60.5-77.2%) of participants completed ≥1 FU survey during the first 6 mo of ET. 25.2% of participants opted out of participation within 6 mo. On multivariate analysis, race was associated with BL survey completion. By race, BL survey completion rate was: 77.9% (W) and 62.5% (B). Mean scores on PROMIS depression, anxiety, fatigue, and sexual function measures at BL, 1 mo, and 3 mo were +/- 0.5 SD of population means. Compared to BL, mean PRO-CTCAE scores for joint pain severity and hot flash frequency worsened at 1 and 3 mo and mean PRO-CTCAE score for vaginal dryness severity worsened at 3 mo (p Citation Format: Karen L Smith, Chenguang Wang, David Lim, Amanda Montanari, Raquel Nunes, Mary J. Wilkinson, Jennifer Y. Sheng, Rima Couzi, John Fetting, Carol Riley, Antonio C. Wolff, Cesar A. Santa-Maria, Katie Papathakis, Lauren Collins-Chase, Christie Hilton, Claire Snyder, Elissa Thorner, Dara Z. Ikejiani, Molly Steimer, Vered Stearns. Feasibility of monitoring symptoms during endocrine therapy with patient reported outcomes collected via smart phone app [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 PS9-14.

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Background Historically, clinical trials involved adding novel agents to standard of care to improve survival. There has been a shift to an individualized approach with testing less intense treatment, particularly in breast cancer where risk of recurrence is low. Little is known about physician perspectives on delivering less intense treatment for patients who are not well represented in clinical trials. Methods Open-ended, individual qualitative interviews with medical oncologists explored their perspectives on trials that test less intense treatment for patients with cancer, with a focus on breast cancer. Interviews were audio-recorded and transcribed. Four independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. Results Of the 39 participating physicians, 61.5% felt comfortable extrapolating, 30.8% were hesitant, and 7.7% would not feel comfortable extrapolating trial outcomes to underrepresented populations. Facilitators of comfort included the sentiment that “biology is biology” (such that the cancer characteristics were what mattered), the strength of the evidence, inclusion of subset analysis on underrepresented populations, and prior experience making decisions with limited data. Barriers to extrapolation included potential harm over the patient’s lifetime, concerns about groups that had minimal participants, application to younger patients, and extending findings to diverse populations. Universally, broader inclusion in trials testing lowering chemotherapy was desired. Conclusions The majority (92%) of physicians reported that they would de-implement treatment for patients poorly represented in clinical trials testing less treatment, while expressing concerns about applicability to specific subpopulations. Further work is needed to increase clinical trial representation of diverse populations to safely and effectively optimize treatment for patients with cancer. Trial registration NCT03248258

Objective This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. Methods Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. Results After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). Conclusions An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

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.

Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea—DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = − 0.74; P = 1.46 × 10–23), representing a previously unidentified mechanism for HFS. This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Purpose: Preclinical data demonstrating androgen receptor (AR)–positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Patients and Methods: Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks. Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.

PURPOSETo update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.METHODSA multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.RECOMMENDATIONSThe Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines .

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.

Introduction: The PREDICT DNA trial is the first prospective, multi-center study aimed at validating cell-free plasma derived circulating tumor DNA (ctDNA) as a biomarker for treatment response and recurrence in early stage, triple-negative or HER2-positive (any hormone receptor status) breast cancer. Its primary aim is to determine the negative predictive value (NPV) of the absence of ctDNA after neoadjuvant therapy (NAT) for the achievement of pathologic complete response (pCR). This study has met its accrual goals and results of the overall trial are anticipated within the next year. The initial PREDICT DNA study design stipulated that tumor specific mutations (TSMs) to be tracked in blood would be identified by next gen sequencing (NGS) of tumor biopsy tissue. A disadvantage of this design is the dependence on adequate biopsy tissue. Recently, the advent of Safe-SeqS technology has enabled robust detection of rare variants using NGS with a sensitivity of approximately 0.05% mutant allele fraction. We employed these new NGS methods to pilot a novel tissue-independent approach to ctDNA detection and monitoring. Objective: The primary objective of this pilot study was to determine whether ultrasensitive NGS using a targeted cancer mutation panel can identify TSMs in ctDNA of early-stage breast cancer patients without the use of biopsy tissue. Methods: The PREDICT DNA trial enrolled 228 women from 22 sites with stage II/III breast cancer for whom standard neoadjuvant therapy was planned. Of these, 58 patients had matched pre-and post-NAT samples available for analysis at the time of this pilot. All pre-NAT samples were analyzed for the presence of TSMs using Sysmex Inostics’ SafeSEQ. Patients with detectable ctDNA before NAT were also evaluated for residual ctDNA after completion of NAT but prior to surgery. Five samples were also tested by digital PCR (BEAMing) for cross-platform comparison. Results: TSMs in ctDNA were identified in 29 of 58 patients (50%) prior to NAT. Of pre-NAT ctDNA(+) patients, TSMs were detected in TP53 (90%) and PIK3CA (10%); three patients (10%) were found to have 2 TSMs. Concordance between SafeSEQ and BEAMing was 100% in five samples tested [3 ctDNA(+), 2 ctDNA(-)]. Of 29 ctDNA(+) patients, 24 (83%) demonstrated reduction or elimination of detectable ctDNA following neoadjuvant therapy, with 16 (55%) converting to ctDNA(-). Conclusion: Identification of TSMs in the plasma of early-stage breast cancer patients without the need for biopsy tissue is feasible using a SafeSEQ cancer mutation panel. Further measures to improve the sensitivity of pre-treatment TSM analysis, such as increased plasma volume input and comprehensive TP53 mutational analysis are currently under investigation. Correlations between clinicopathologic factors with ctDNA detection and burden, as well as the NPV of post-NAT ctDNA for pCR and residual cancer burden, will be reported at the time of abstract presentation. NH and HP contributed equally to this work. Citation Format: Natasha Hunter, Heather Parsons, Alexander Sherry, Daniel Shinn, Dong Ho Shin, Alex Cole, Giovanni Cragnotti, Taylor Groginski, Margaret Leathers, Andrea L Richardson, Pedram Argani, Antonio Wolff, Leslie Cope, Dan Edelstein, Frank Holtrup, Hilary Sloane, Bapsi Chakravarthy, Vered Stearns, Ben H Park. TBCRC 040: Pathologic response evaluation and detection in circulating tumor DNA (PREDICT DNA): Initial results piloting a tissue-biopsy independent method of identifying and monitoring tumor-specific mutations in early stage 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 P6-10-05.

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.

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2+ breast cancer. The predictive value of TILs, TIL subsets, and other immune cells in patients receiving chemotherapy-sparing lapatinib plus trastuzumab treatment is unclear. Experimental Design: Hematoxylin and eosin–stained slides (n = 59) were used to score stromal (s-)TILs from pretreatment biopsies of patients enrolled in the neoadjuvant TBCRC006 trial of 12-week lapatinib plus trastuzumab therapy (plus endocrine therapy for ER+ tumors). A 60% threshold was used to define lymphocyte-predominant breast cancer (LPBC). Multiplexed immunofluorescence (m-IF) staining (CD4, CD8, CD20, CD68, and FoxP3) and multispectral imaging were performed to characterize immune infiltrates in single formalin-fixed paraffin-embedded slides (n = 33). Results: The pathologic complete response (pCR) rate was numerically higher in patients with LPBC compared with patients with non-LPBC (50% vs. 19%, P = 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR = 7% vs. 50%, for cluster 1 vs. 2 respectively; P = 0.01). In multivariable analysis, cluster 2, characterized by high CD4+, CD8+, CD20+ s-TILs, and high CD20+ intratumoral TILs, was independently associated with a higher pCR rate (P = 0.03). Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by s-CD4, intratumoral (i-) CD4, and i-CD20+ TILs. Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2+ breast cancer. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response.

Purpose.—To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline.Methods.—A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.Recommendations.—The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.

We lack tools to risk-stratify triple-negative breast cancer (TNBC). Our goal was to develop molecular tools to predict disease recurrence. Methylation array analysis was performed on 110 samples treated by locoregional therapy obtained from institutional cohorts. Discovered marker sets were then tested by Kaplan−Meier analyses in a prospectively collected TNBC cohort of 49 samples from the no-chemotherapy arms of IBCSG trials VIII and IX, and by logistic regression in a chemotherapy-treated cohort of 121 TNBCs from combined IBCSG trials and institutional repositories. High methylation was associated with shorter recurrence-free interval in the no-chemotherapy arm of the IBCSG studies, as well as in the chemotherapy-treated patients within the combined institutional and IBCSG chemotherapy cohorts (100 marker panel, p = 0.002; 30 marker panel, p = 0.05). Chromosome 19 sites were enriched among these loci. In conclusion, our hypermethylation signatures identify increased recurrence risk independent of whether patients receive chemotherapy.

We assessed breast cancer clinicians' perspectives on how the COVID-19 pandemic and increased use of telehealth affected their clinical communication about sexual heath.Breast cancer clinicians participating in a sexual health communication intervention study (N = 29; 76% female; 66% oncologists; 34% advanced practice clinicians) completed an online survey. Data analysis consisted of descriptive statistics and thematic analysis.All clinicians were using telehealth, with most (66%) using it for up to half of their clinic appointments. Although only 14% of clinicians reported having shorter clinic visits, 28% reported having less time to discuss sexual health; 69% reported no change; and 3% said they had more time. Forty-one percent reported sexual health was less of a priority; 55% reported no change; and 3% said it was more of a priority. Thirty-five percent reported telehealth was less conducive to discussing sexual health; 59% reported no change; and 7% reported more conducive. Qualitative analysis revealed key issues underlying the perceived impact of the pandemic on discussions of sexual health including heightened clinician discomfort discussing such issues via telehealth, the less personal nature and privacy issues in telehealth visits, increased concerns about risk of COVID-19 infection and other health concerns (e.g., missing recurrence, mental health) taking priority, and clinician-perceived patient factors (e.g., discomfort, decreased priority) in discussing sexual concerns.Pandemic-related changes in breast cancer clinicians' practice could be exacerbating challenges to discussing sexual health. Methods for integrating sexual health into cancer care are needed, regardless of the mode of delivery.

ImportanceThe pathologic complete response (pCR) is supported by regulatory agencies as a surrogate end point for long-term patients’ clinical outcomes in the accelerated approval process of new drugs tested in neoadjuvant randomized clinical trials (RCTs) for early breast cancer (BC). However, a meaningful association between pCR and patients’ survival has been proven only at the patient level (ie, significantly better survival of patients who achieved pCR compared with those who did not), but not at trial level (ie, poor association between degree of improvement in pCR rate and survival reported across trials).ObservationsWe critically discuss the potential reasons of such discrepancy between pCR surrogacy value at the patient and trial level, as well as the relevant implications for both clinical research and drug regulatory policy. We also describe alternative surrogate end points, including combined end points that jointly analyzed pathological response and event-free survival data, or the assessment of circulating tumor DNA (ctDNA). Such proposed surrogate end points could overcome limits of pCR and provide a reasonable trade-off between the 2 conflicting needs to have access to effective therapies rapidly, and to reliably assess patients’ clinical benefit.Conclusions and RelevanceUsing surrogate end points to grant drug approvals is justified only when they can provide accurate prediction of a drug’s effect on the long-term patient outcomes. Evidence currently available does not support pCR used alone as a reliable surrogate end point in regulatory neoadjuvant RCTs for BC. The surrogacy value at trial level of potentially more robust surrogate end points needs to be urgently tested.

254 Background: As the combination of systemic and targeted chemotherapies is associated with severe adverse side effects and long-term health complications, there is interest in reducing treatment intensity for patients with early-stage breast cancer (EBC). Currently, this approach is being described as “de-escalation,” though there is some concern that this language and framing are not well understood or preferred by patients. Methods: We collected qualitative interview data from twenty-four patients with Stage II-III breast cancer and sixteen patient advocates. Interviews explored interest in participation in clinical trials testing reduced amounts of chemotherapy, reactions to the word “de-escalation,” and preferred ways to describe this approach and its anticipated benefits. Interviews were audio-recorded and transcribed, and researchers used qualitative content analysis to code for dominant themes. Results: Twenty-three participants (57.5%) expressed interest in participating in a trial of reduced chemotherapy. However, 60% of participants had a negative response to the word “de-escalation,” including 78% of respondents that said they were interested in the concept. To describe this approach, respondents tend to prefer words like “personalization,” “optimization,” or “reduced chemotherapy.” Participants also expressed the importance of provider-patient communication, clear and simple language, sharing the decision-making process, and continued support throughout and after treatment in their consideration of trials testing lower amounts of chemotherapy. Conclusions: Among individuals with EBC, there is significant interest in alleviating treatment-related toxicity by reducing chemotherapeutic intensity. Patients are more apt to feel comfortable participating in trials testing this approach if they are framed in terms of customizing treatment to the individual patient and added benefit—reduced toxicities, higher quality of life during treatment and lower risk of long-term complications—rather than in terms of taking treatments away or doing less than the standard of care. “De-escalation” is not an ideal word to describe these trials as many associate this word with giving up in the war against cancer. Instead, participants prefer positive, patient-centered language. This information will be useful to providers in considering how best to describe de-escalation clinical trials to eligible patients in ways that avoid therapeutic misconception and facilitate the shared decision-making process regarding treatment.

99 Background: Optimization clinical trials testing less intense treatments are becoming more prominent in oncology due to the availability of better prognostic tools and targeted therapies. In addition to previously documented barriers, these trials are likely to face new barriers from engaging racially diverse populations due to the potential of an increased recurrence risk with reducing treatment. However, little is known about the role of race in decision-making for optimization clinical trials amongst physicians and patients. Methods: This qualitative study included a subset analysis on the influence of race in decision-making for participation in trials testing less chemotherapy. This analysis is part of a larger study, which included semi-structured interviews with patients, patient advocates, and physicians assessing barriers and facilitators to trial participation. Interviews were transcribed, and four coders evaluated transcripts for key themes and exemplary quotes using NVivo. Results: 79 participants (24 patients with breast cancer, 16 patient advocates, and 39 physicians) participated; 30% of patients and patient advocates and 26% of physicians were BIPOC (Black, Indigenous, and People of Color). Several key barriers traditionally associated with Black race were noted amongst both patients and physicians, including aggressive biology (e.g. triple negative breast cancer), younger age, socioeconomic challenges, and lack of trust in physicians and clinical trials. One physician noted, “Taking someone who already has a mistrust of medical care and talking to them about a trial of cutting medical care back, it’s challenging.” While some physicians explicitly acknowledged the role of race in decision-making, often linking race to these barriers, the majority of physicians independently highlighted these barriers while denying the explicit impact of race. Black patients noted similar barriers including emphasizing the role of having triple negative breast cancer, being young, the influence of financial strain, and medical mistrust. One Black patient commented, “I was a triple negative, and that kind was more prone to African American women, usually we don’t really survive from it as well as other races do.” Another Black woman commented, “I had a lot of family and friends that were worried that I was going to be a “guinea pig”. In contrast, White patients heavily emphasized the role of trust in their physicians when making decisions. A White woman stated the following, “I would have done whatever they (doctors) told me was the best thing to do.”. Conclusions: Factors associated with Black race can play both an overt and subconscious role in patient and provider decision-making about participation in optimization clinical trials. Multi-level interventions are needed to address these specific barriers to ensure representative participation in clinical trials for all patient populations.

349 Background: Biomarkers are regularly utilized to select treatment within cancer clinical trials. However, there remains a lack of understanding regarding physician perspectives on what data is needed for physicians to comfortably use these markers to escalate or de-escalate chemotherapy. Methods: Semi-structured qualitative interviews with medical oncologists from different academic and community-based cancer centers were conducted to investigate perspectives on the utilization of biomarkers to de-escalate chemotherapy. Key topics explored included: (1) physician preference for biology-based (e.g. genomic profiles) vs. response-based (e.g. complete pathologic response) biomarkers, and (2) importance of personal familiarity with biomarkers. Interviews were audio-recorded and transcribed. Two independent coders analyzed transcripts using a constant comparative method in NVivo to identify major themes. Analysis was stratified by practice-type to elucidate differences between oncologists at academic and community practices. Results: Of the 39 participating physicians, 51% practiced in an academic setting and 49% practiced in a community setting. The majority of physicians (67% overall, 77% community, 59% academic) did not have a preference for biology-based vs. response-based biomarkers, if the data is equally strong and clinical use is appropriate for the clinical context (e.g. patient subtype). Many physicians were reassured by achieving a real-time therapeutic response, with 23% of physicians preferring response-based biomarkers. One physician stated, “I am still more comfortable with a real-time, well-validated biomarker, response marker, than I am with an overall predictive marker for a population”. In contrast, 10% (all academic) preferred biology-based biomarkers. One physician commented “I think the biology is probably more attractive because that potentially allows you to avoid treatment, whereas pathCR they've already had to get treatment to get there”. The majority of academic physicians (55%) felt that strong data was more important than personal familiarity with regards to implementation of novel biomarkers, as noted by one who stated, “As long as there's good data, I don't care.” 15% of community physicians shared a similar view. The majority of community physicians (54%) voiced familiarity to be more important in their comfort with biomarker use as noted by one physician who stated, “I think things I’m already familiar with, I'm more inclined to feel good about”. 18% of academic physicians held a similar perspective. Conclusions: Academic and community physicians’ perspectives regarding use of novel biomarkers overlap, with multiple factors playing a role in how these biomarkers are used in decision-making. Future research is needed to understand the impact of biomarker selection on clinical trial enrollment.

97 Background: In order to maintain safety, clinical trial activities have been modified during the COVID-19 pandemic. As part of the TBCRC 057 survey, we assessed how pandemic-related modifications to trial activities affect breast cancer patients’ willingness to participate in clinical trials. Methods: US residents with breast cancer were eligible to complete the online survey 8/6/21 – 9/30/21. Respondents rated whether each of 11 modifications to clinical trial activities would affect their decision to participate in a trial during or after the pandemic. Items evaluated modifications that involved changing the location of trial activities to closer to home, switching trial activities to telemedicine and making the trial schedule more flexible and convenient. Response options were “much less likely to participate”, “somewhat less likely to participate”, “would not affect my decision whether or not to participate”, “somewhat more likely to participate” and “much more likely to participate”. Current trial participants were asked to consider how modifications would affect their decision to participate in another trial. Results are reported descriptively. Results: Among 385 respondents, median age was 52 (range 25-85), 88.6% were non-Hispanic White, 52.5% had metastatic disease, 93% were receiving active treatment, 48.6% received care at an academic center and 9.6% were current trial participants. Changing location of trial activities was viewed favorably, with 70.2%, 64.6% and 54.1% of respondents indicating they would be much or somewhat more likely to participate if they could complete trial blood tests, x-ray tests or doctor visits closer to home, respectively. Similarly, the option to complete trial activities electronically was viewed favorably, with 59.6%, 58.6% and 60.9% of respondents indicating they would be much or somewhat more likely to participate if they could complete trial doctor visits, consent and questionnaires via telemedicine, respectively. With regard to modifications to make the trial schedule more flexible and convenient, respondent feedback was also favorable. 71.4%, 67.7% and 82.4% of respondents indicated that requiring study site visits no more than once per 3 weeks, widening windows for trial activities and offering home delivery of oral study medications, respectively, would make them much or somewhat more likely to participate. Finally, 30.4% and 51.7% indicated that the flexibility to opt-out of research-only blood tests and biopsies, respectively, would make them much or somewhat more likely to participate. Conclusions: Patients view modifications to trial activities implemented during the pandemic favorably. Trials should be flexible and the option to conduct study activities close to home or electronically when possible should be maintained during the pandemic and beyond.

PURPOSE Younger women are at risk for depression and related symptoms following breast cancer. The Pathways to Wellness study, a randomized, multi-institution, three-arm trial, tested the efficacy of two behavioral interventions for younger breast cancer survivors with elevated depressive symptoms: mindful awareness practices (MAPs) and survivorship education (SE) (Clincaltrials.gov identifier: NCT03025139 ). METHODS Women diagnosed with breast cancer at or before 50 years of age who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments were conducted preintervention and postintervention and at 3-month and 6-month postintervention follow-ups. Analyses compared each intervention to WLC using linear mixed models. The primary outcome was change in depressive symptoms from preintervention to postintervention on the Center for Epidemiologic Studies-Depression Scale; secondary outcomes included change in fatigue, insomnia, and vasomotor symptoms. RESULTS Two hundred forty-seven women (median age = 46 years) were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs and SE led to significant decreases in depressive symptoms from preintervention to postintervention relative to WLC (mean change relative to WLC [95% CI]: MAPs, –4.7 [–7.5 to –1.9]; SE, –4.0 [–6.9 to –1.1]), which persisted at 6-month follow-up for MAPs (mean change relative to WLC [95% CI]: MAPs, –3.7 [–6.6 to –0.8]; SE, –2.8 [–5.9 to 0.2]). MAPs, but not SE, also had beneficial effects on fatigue, insomnia, and vasomotor symptoms that persisted at 6-month follow-up ( P < .05). CONCLUSION Mindfulness meditation and SE reduced depressive symptoms in younger breast cancer survivors. These interventions can be widely disseminated over virtual platforms and have significant potential benefit for quality of life and overall survivorship in this vulnerable group.

Background: Most breast cancer clinicians lack training to counsel patients about sexual concerns. The purpose of this study was to assess the feasibility, acceptability, and preliminary effects of a mobile learning (mLearning) intervention (improving Sexual Health and Augmenting Relationships through Education [iSHARE]) aimed at enhancing breast cancer clinicians’ knowledge of, beliefs about, and comfort with discussing patients’ sexual health concerns. Methods: Clinicians listened to a 2-part educational podcast series offering information on breast cancer–related sexual health concerns and effective communication on the topic, which consisted of interviews with expert guests. Intervention feasibility was assessed through rates of enrollment, retention, and intervention completion, with benchmarks of 40%, 70%, and 60%, respectively. Acceptability was assessed through program evaluations, with 75% of clinicians rating the intervention favorably (eg, relevance, satisfaction) signifying acceptability. Clinicians self-reported their knowledge about breast cancer–related sexual health concerns, beliefs (ie, self-efficacy for discussing sexual health concerns), and comfort with discussing sexual concerns measured at preintervention and postintervention. Qualitative analysis examined clinicians’ perceptions of lessons learned from the intervention. Results: A total of 32 breast cancer clinicians enrolled (46% of those invited; 97% of those who responded and screened eligible), 30 (94%) completed both the intervention and study surveys, and 80% rated the intervention favorably, demonstrating feasibility and acceptability. Results showed positive trends for improvement in clinician knowledge, beliefs, and comfort with discussing sexual health concerns. Clinicians reported key lessons learned, including taking a proactive approach to discussing sexual health concerns, normalizing the topic, addressing vaginal health, sending the message that help is available, and assessing sexual health concerns with patients from different backgrounds. Conclusions: Breast cancer clinicians were amenable to participating in the iSHARE intervention and found it useful. iSHARE showed promise for improving clinician’s knowledge and comfort discussing patients’ sexual health concerns. A larger trial is required to demonstrate efficacy. Future studies should also examine whether iSHARE can improve patient–clinician communication and address patients’ sexual concerns.

PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

BACKGROUND: There are limited data from clinical trials describing preoperative MRI features and performance in the evaluation of mammographically detected ductal carcinoma in situ (DCIS). PURPOSE: To report qualitative MRI features of DCIS, MRI performance in the identification of additional disease, and associations of imaging features with pathologic, genomic, and surgical outcomes from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) E4112 trial. MATERIALS AND METHODS: Secondary analyses of a multicenter prospective clinical trial from the ECOG-ACRIN Cancer Research Group included women with DCIS diagnosed with conventional imaging techniques (mammography and US), confirmed via core-needle biopsy (CNB), and enrolled between March 2015 and April 2016 who were candidates for wide local excision (WLE) based on conventional imaging and clinical examination results. DCIS MRI features and pathologic features from CNB and excision were recorded. Each woman without invasive upgrade of the index DCIS at WLE received a 12-gene DCIS score. MRI performance metrics were calculated. Associations of imaging features with invasive upgrade, dichotomized DCIS score (

PURPOSE Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. PATIENTS AND METHODS Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. RESULTS Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. CONCLUSION Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor outcomes among breast cancers. A subset of TNBCs demonstrates an aggressive course with marked chemoresistance, rapid distant metastatic spread, and poor survival. The clinicopathologic and sociodemographic features associated with rapid relapse among TNBCs remain poorly understood. Primary Objective: To evaluate the relationship between clinicopathologic and sociodemographic features with rapid relapse in TNBC (rrTNBC). Methods: This large multi-institutional study analyzed a cohort of breast cancer patients diagnosed with TNBC who received treatment at one of ten academic centers that previously participated in a National Comprehensive Cancer Network (NCCN) outcomes database between 1998 and 2012. We defined rrTNBC as a distant metastatic recurrence event or death from any cause ≤24 months after diagnosis. We included patients with ≥2 years follow-up or had suffered a survival event within that timeframe. We excluded patients with de novo metastatic disease and those who did not receive chemotherapy. We randomly divided the total dataset into 70% training and 30% validation cohorts, balanced by the number of rrTNBC events. Covariates included study site, age at diagnosis, body mass index (BMI), race/ethnicity, education, median annual household income (2000 census tract), insurance type (Managed Care, Medicare, Medicaid, and Other), Charlson comorbidity index, tumor stage and grade at diagnosis, and adjuvant radiation treatment. Logistic regression was performed among the training dataset univariately for associations with rapid relapse vs. not. Features with a p-value Results: Among 41,839 patients with invasive breast cancer treated in these ten centers, 5256 had TNBC (12.6%), among whom 3016 had adequate follow-up to be included in the analysis. Bivariable analyses in the training cohort (n=2112) identified tumor stage at diagnosis, insurance type, age at diagnosis, BMI, race, and income to be associated with rrTNBC events (p15x increased risk of rapid relapse (adjusted OR [95% CI]: 16.5 [10.3, 26.4]; p Conclusion: Advanced tumor stage at diagnosis was the most influential predictor of rapid relapse among patients who had TNBC, while type of insurance remains an independent predictor in training and validation cohorts. Given the known association of sociodemographic disparities with tumor stage, further study of underlying causes and potential interventions to reduce rapid relapse of TNBC is warranted. Citation Format: Sarah Asad, Carlos H. Barcenas, Richard J. Bleicher, Adam L. Cohen, Sara H. Javid, Ellis G. Levine, Nancy U. Lin, Beverly Moy, Joyce Niland, Antonio C. Wolff, Michael J. Hassett, Daniel G. Stover. Factors associated with rapid relapse in triple negative breast cancer: A multi-institution study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-02.

Members of the Translational Breast Cancer Research Consortium conducted an expert-driven literature review to identify a list of domains and to evaluate potential measures of these domains for inclusion in a list of preferred measures. Measures were included if they were easily available, free of charge, and had acceptable psychometrics based on published peer-reviewed analyses. A total of 22 domains and 52 measures were identified during the selection process. Taken together, these measures form a reliable and validated list of measurement tools that are easily available and used in multiple cancer trials to assess patient-reported outcomes in relevant patients.

Despite persistent inequities in access to care and treatments, advances in combined modality care have led to a steady improvement in outcomes for breast cancer patients across the globe. When estimating the magnitude of clinical benefit of therapies, providers and patients must contend with a multitude of factors that impact treatment decisions and can have long-term effects on quality of life and survival. These include commonly described early toxicities, like aromatase inhibitor-associated musculoskeletal syndrome and neuropathy. But longer-term comorbidities often observed among cancer survivors including weight gain, obesity, infertility, psychological distress, sexual dysfunction, second cancers, bone loss, and body image issues can have lasting effects on quality of life. Equally important, system-level factors such as access to care and resource allocation can have a systemic impact on survival and on the quality of survivorship. Financial toxicity including underemployment can have a lasting impact on patients and caregivers. The resulting disparities in access to treatment can help explain much of the observed variability in outcomes, even within high-income countries like the US. This article revisits some of secondary effects from therapies discussed in a prior 2015 review article, along with other impediments to the optimal delivery of breast cancer care that can affect patients anywhere.

Purpose:An unmet need in low-resource countries is an automated breast cancer detection assay to prioritize women who should undergo core breast biopsy and pathologic review. Therefore, we sought to identify and validate a panel of methylated DNA markers to discriminate between cancer and benign breast lesions using cells obtained by fine-needle aspiration (FNA).Experimental Design: Two case–control studies were conducted comparing cancer and benign breast tissue identified from clinical repositories in the United States, China, and South Africa for marker selection/training (N = 226) and testing (N = 246). Twenty-five methylated markers were assayed by Quantitative Multiplex-Methylation-Specific PCR (QM-MSP) to select and test a cancer-specific panel. Next, a pilot study was conducted on archival FNAs (49 benign, 24 invasive) from women with mammographically suspicious lesions using a newly developed, 5-hour, quantitative, automated cartridge system. We calculated sensitivity, specificity, and area under the receiver-operating characteristic curve (AUC) compared with histopathology for the marker panel.Results:In the discovery cohort, 10 of 25 markers were selected that were highly methylated in breast cancer compared with benign tissues by QM-MSP. In the independent test cohort, this panel yielded an AUC of 0.937 (95% CI = 0.900–0.970). In the FNA pilot, we achieved an AUC of 0.960 (95% CI = 0.883–1.0) using the automated cartridge system.Conclusions:We developed and piloted a fast and accurate methylation marker–based automated cartridge system to detect breast cancer in FNA samples. This quick ancillary test has the potential to prioritize cancer over benign tissues for expedited pathologic evaluation in poorly resourced countries.

Survivorship care plans (SCPs) provide key information about cancer treatment history and follow-up recommendations. We describe the completeness of breast cancer SCPs and evaluate guideline concordance of follow-up recommendations. We analyzed 149 breast cancer SCPs from two sites, abstracting demographics, cancer/treatment details, surveillance plans, and health promotion advice. SCP recommendations and provided information were compared to American Cancer Society/American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines. SCP information provided in > 90% of the plans included patient age; relevant providers; cancer stage; treatment details; and physical exam, mammogram, and health promotion recommendations. SCP components completed less frequently included post-treatment symptoms/side effects (67%). All SCPs at the community site were uniform but had the potential for oversurveillance if visits occurred every 3 months in years 1–2 or every 6 months in years 3–5 with multiple cancer providers. The academic site recommended three predominant patterns of follow-up: (1) primary care provider every 6–12 months; (2) cancer team every 3–6 months (year 1), every 6–12 months (years 4–5); and (3) alternating oncology providers every 3–6 months (years 1–2) then every 6 months. Compared to guidelines, these patterns recommend under- and oversurveillance at various times. Mammography recommendations showed guideline concordance (annual) for 84%, oversurveillance for 10%, and were incomplete for 6%. SCPs of only 12/79 (15%) women on aromatase inhibitors recommended guideline-concordant bone density testing. SCP content is more complete for demographic and treatment summary information but has follow-up recommendation gaps. Efforts to improve follow-up recommendations are needed.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio

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.

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake values corrected for lean body mass (SULmax) on [18F]fluorodeoxyglucose positron emission tomography/computed tomography would predict pathologic complete response (pCR) to neoadjuvant pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II/III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. [18F]Fluorodeoxyglucose positron emission tomography/computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percentage of change in SULmax by C1D15 predicting pCR is less than or equal to 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 34%. Receiver operating characteristic analysis yielded an area under the curve of 0.76 (90% CI, 0.67 to 0.85), which rejected the null hypothesis. Between patients who obtained pCR versus not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 33.5%; P < .001), an SULmax reduction greater than or equal to 40% was more prevalent (86% v 46%; P < .001; negative predictive value, 88%; positive predictive value, 49%), and a significant difference in median C1D15 SULmax (1.6 v 3.9; P < .001) and higher proportion of C1D15 SULmax less than or equal to 3 (93% v 38%; P < .001; negative predictive value, 94%; positive predictive value, 55%) were observed. CONCLUSION Early changes in SULmax predict response to four cycles of PT in estrogen receptor–negative, HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate a more tailored approach to therapy in this setting.

Background Addition of the cyclin dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib to endocrine therapy in the first and later line settings significantly improves progression free survival (PFS) in patients with HR+ MBC. The primary toxicity is neutropenia without an increase in febrile neutropenia. TBCRC035 explored rates of neutropenia in patients who had received prior chemotherapy for MBC with 2 dose levels of palbociclib, and correlated changes in retinoblastoma protein phosphorylation (pRB) and Ki67 expression in proliferating keratinocytes and tumor with response. Methods TBCRC035 is a 1:1 randomized multicenter phase II study evaluating palbociclib at either 125 or 100 mg in combination with physician choice fulvestrant or tamoxifen. Eligible patients (pts) with HR+ MBC had received >1 but Results 70 pts were enrolled (fully accrued); 35 randomized to 100 vs 125 mg of palbociclib respectively; data for the last 3 pts on the 125 mg arm is pending. Grade 3/4 neutropenia was more common in the 125 mg vs the 100 mg arm (56 vs 34%); dose adjustments for adverse events (AEs) occurred in 47 vs 43%, 4 vs 0 pts discontinued treatment due to AEs. Grade 3 febrile neutropenia was rare (1 patient each arm). Median duration of treatment was 5.2 vs 7.2 months. Response data and correlation with changes in pRB and Ki67 expression in skin and tumor by treatment arm will be reported. Conclusion In pts with prior chemotherapy for HR+ MBC, treatment with 100 mg of palbociclib in patients is associated with a lower rate of > grade 3 neutropenia compared to 125 mg. Correlation of response by dose with pRB and Ki67 has the potential to inform palbociclib dosing and reduce toxicity for pts with HR+ MBC. Citation Format: Rugo HS, Mayer EL, Storniolo AM, Isaacs C, Mayer I, Stearns V, Nanda R, Nangia J, Wabl C, Deluca A, Kochupurakkal B, Wolff AC, Shapiro GI. Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive (HR+) metastatic breast cancer (MBC) with prior chemotherapy for advanced disease (TBCRC 035) A phase II study with pharmacodynamics markers [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 PD2-12.

BACKGROUND. Chemotherapy remains the treatment mainstay for triple-negative breast cancer (TNBC). Nevertheless, randomized trials have shown that not all TNBC require it, nor does it benefit all patients that receive it. Molecular tools to risk-stratify TNBC are currently lacking. In light of the importance of epigenetic processes modulating gene expression, we performed an array-based genome-wide DNA methylation search in well-documented institutional and clinical trial cohorts of TNBC for markers that can distinguish breast cancers with a favorable natural history from those with a high risk of recurrence. METHODS. We performed an array-based genome-wide DNA methylation survey of well-documented institutional and clinical trial cohorts of TNBC and conducted molecular marker discovery on institutional TNBCs (115 patient samples; 53 recurrences) treated by locoregional therapy (LRT) alone. The identified hypermethylated gene signatures were then tested in a TNBC cohort (50 patient samples; 16 recurrences) from the no chemotherapy arms of IBCSG trials VIII and IX, and in a separate combined cohort of TNBCs (131 patient samples; 33 recurrences) treated with chemotherapy from an institutional repository and from IBCSG trials VIII and IX. Cross platform validation was conducted using quantitative multiplexed methylation specific PCR (QM-MSP) on hypermethylated markers in samples from both the Discovery Set and IBCSG LRT Test Set. RESULTS. We identified methylation signatures in the discovery cohort consisting of 100 or 30 CpG probes that discriminated patients who remained recurrence-free from those with recurrent disease. These signatures were then tested in the IBCSG no chemotherapy cohort, and we found that hypermethylation was associated with shorter recurrence-free interval (RFI). A significant association of both 100 CpG (P CONCLUSIONS. Methylation markers may be of prognostic importance in TNBC and our findings should be validated in additional clinical trial cohorts. Citation Format: Fackler MJ, Cho SS, Cope LM, Gabrielson E, Wilsbach K, Lynch C, Marks JR, Geradts J, Regan MM, Viale G, Wolff AC, Umbricht CB, Sukumar S. DNA methylation markers predict recurrence-free interval in triple-negative breast cancer [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 P4-08-09.

Background We investigated the clinical outcomes and behavior of HER2+ EBC according to centrally tested HR status in pts treated with modern chemotherapy (CT) and trastuzumab (T)-based regimens. Patients and methods ALTTO is an international phase 3 trial in HER2+ EBC pts randomized to 4 adjuvant anti-HER2 treatment arms: T alone, lapatinib (L) alone, their sequence (T->L) or their combination (T+L). Pts in the L alone arm were excluded from the present analysis. HER2 and HR status were centrally tested for all patients. HER2 status was defined based on the 2007 ASCO/CAP guidelines. HR-positive (HR+) was defined as ≥1% tumor cells with expression of estrogen (ER) and/or progesterone receptors.We investigated the prognosis of pts with HR+ or negative (HR-) HER2+ EBC, the risk of developing early (years 0-5) and late (years 6-8) recurrences, the factors impacting this risk, and the patterns of relapse according to HR status. Univariate and multivariate Cox proportional hazard models were used to compare hazard rates within the HR subgroups; a conditional landmark analysis was conducted to investigate late recurrences. For the hazard ratios for HR status, an interaction between log(time) and HR status was included as proportional hazard assumption was not satisfied. Results This analysis included 6,271 HER2+ pts of whom 3,601 (57%) had HR+ and 2,670(43%) HR- EBC. Median follow-up was 6.93 years (range 6.81-6.96). 5-year disease-free survival (DFS) was 86% (85-87) in HR+ and 83% (82-85) in HR- pts; 8-year DFS was 80% (78-81) in HR+ and 79% (77-81) in HR- pts. The mean annual hazards of recurrence in years 0-5 were 3% in HR+ and 4% in HR- pts, while in years 6-8 they were 3% in HR+ and 2% in HR- pts. The hazard ratios for HR status (ref=HR-) were 0.60 (0.51-0.72) overall, 0.74 (0.65-0.85) for years 0-5 and 1.61 (1.17-2.24) for years 6-8. In HR+ pts, risk factors for recurrence overall were age ≥65 (p=0.01), tumor size pT3-4 (p In HR- pts, risk factors for recurrence overall were BMI (obesity or underweight; p=0.01), pT3-4 (p HR+ pts had lower incidence of visceral disease (58.8% vs. 69.6%; p=0.005) and lung metastasis (18.5% vs. 27.8%; p=0.006); bone was the most common site of first recurrence (30%). Conclusions This large analysis of centrally tested HR+ and HR- HER2+ EBC provides strong evidence on the existence of two different diseases within the HER2+ population based on HR expression. These up-to-date estimates of pts outcomes after modern CT and T-based regimens may be used as “historical control” for the design of future de-escalation or escalation trials separately in HR+ and HR- HER2+ EBC pts. Citation Format: Lambertini M, Campbell C, Gelber RD, Viale G, McCullough A, Tonghua L, Hilbers F, Korde LA, Werner O, Chumsri S, Jackisch C, Wolff AC, Vaz-Luis I, Ferreira AR, Prat A, Moreno Aspitia A, Piccart M, Loi S, de Azambuja E. Dissecting the effect of hormone receptor (HR) status expression in patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Exploratory analysis from the ALTTO (BIG 2-06) trial [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 P2-08-14.

Background: Triple negative breast cancer (TNBC) accounts for 10-17% of all breast cancer and is more likely to be of higher histological grade, poorly differentiated, associated with a higher recurrence rate and with decreased overall survival. The clinical course of a TNBC patient remains difficult to predict, as tumors with homogenous morphological characteristics may vary in response to therapy and have divergent outcomes. Therefore, additional analytical methods are needed to better classify TNBC. Our goal is to refine the analysis of methylome datasets to derive reliable molecular signatures that can distinguish TNBC patients with good outcomes who may benefit from less aggressive treatment, from those with poor outcomes who would be candidates for more aggressive treatments. Methods: Our laboratory has conducted and reported, in this meeting, results from analysis of 450k methylation array data on a discovery set of 53 high-risk TNBC cases and 62 low-risk controls treated by locoregional therapy alone, as well as 5 normal breast tissue samples. High-risk cases were defined as patients that relapsed within 0.5 to 6.5 years from the time of diagnosis, while low-risk controls had no relapse and >4 year recurrence-free intervals (RFI). In this work, we devised and applied a novel methylation biomarker discovery program named Hypermethylated Outlier Detector (HOD) that emphasizes the selection of highly methylated markers in cases compared to controls, to find a high-risk signature in the TNBC discovery set. The methylation signature identified by HOD was interrogated in a test set of 50 TNBCs (with 16 recurrences) that did not receive chemotherapy, and in a second test set of 131 TNBCs (with 33 recurrences) that did receive chemotherapy. Results: HOD identified 39 hypermethylated markers (beta >0.20) that could accurately distinguish between the high-risk cases and the low-risk controls in the discovery set of TNBCs (n=115) treated with locoregional therapy alone. In the test set of TNBC (n=50) with no chemotherapy the 39 markers distinguished high from low risk individuals (likelihood ratio test P=0.049). In a second test set of TNBC (n=131) that received chemotherapy the 39 hypermethylated markers again distinguished high from low risk individuals (likelihood ratio test P=0.0043). Conclusions: We have presented evidence that a methylation signature identified by HOD can be used to identify TNBC patients that have a high-risk of relapse regardless of receiving chemotherapy. This methylation signature could potentially be used to inform physician decisions on therapeutic strategies for TNBC patients. This could ultimately lead to less aggressive treatment given to patients possessing a methylation profile consistent with a better prognosis. Conversely, patients with hypermethylation in the 39 markers will likely benefit from a more aggressive course of treatment. Citation Format: Downs BM, Cope LM, Fackler MJ, Cho S, Wolff AC, Regan MM, Sukumar S, Umbricht CB. A new method of data analysis to derive DNA methylation signatures that stratify risk of recurrence in triple negative breast cancer [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 P5-12-04.

Background: Cardiac toxicity (CT) is a rare late effect of anthracycline therapy for breast cancer (BC). Statins may attenuate the CT of anthracyclines. Myocardial strain can detect subclinical CT before ejection fraction (EF) declines. Global longitudinal strain (GLS) ≥-19% and relative change (RelΔ) in GLS≥11% predict future decline in EF. We conducted a pilot study to evaluate the effect of simvastatin on GLS in BC patients receiving anthracyclines. Methods: We enrolled women with stage I-III BC planning doxorubicin/cyclophosphamide (AC) x 4. Women with heart disease or taking a statin were excluded. Participants were randomized 1:1 to simvastatin 40 mg daily x 24 weeks (wk) + AC or to AC alone. We performed echo with strain 5 times: baseline (BL), pre-AC#2, 1-3 wk after AC#4, 24 wk after AC #1 and 52 wk after AC#1. The primary endpoint was the mean absolute change (|Δ|) in GLS from BL to 1-3 wk after AC#4. Secondary endpoints included RelΔ in GLS, feasibility and safety. We used two-sample t-tests to compare mean changes in GLS and Fisher's exact test to compare dichotomized GLS values. The study closed early due to loss of staff. Results: Of 31 patients, 15 (48%) received simvastatin+AC. Mean age was 46 years; 71% pre-menopausal, 61% white and 32% black. There were no significant differences in BL cardiovascular risk factors between the arms. After AC, 3 HER2+ patients received trastuzumab. There were no grade 3-4 AEs with simvastatin. Common grade 1-2 AEs included myalgia (20%), elevated AST (27%) and elevated ALT (53%). One patient in the AC arm died from heart failure with low EF 2 months after having a normal echo 1-3 wk after AC#4. The rate of missing echos was 14%. Of 133 completed echos, 124 (93%) were evaluable for GLS. Mean GLS was 60% at all times in both arms. Among 27 patients evaluable for the primary endpoint, there was no significant difference in mean |Δ| in GLS from BL to 1-3 wk after AC#4 between the arms (Simvastatin+AC: 0.42%; AC: 1.11%, p=0.57). In addition, there were no differences in the mean|Δ| in GLS from BL to any other time between the arms (all p>0.1). The proportion of patients with GLS0.05). The proportion of patients with RelΔ in GLS≥11% from BL was lower in the simvastatin+AC arm than in the AC arm pre-AC#2 (13% vs 19%), 1-3 wk after AC#4 (20% vs 44%) and 24 wk after AC#1(27% vs 31%) (all p>0.05). Conclusion: Simvastatin did not result in a statistically significant difference in the mean |Δ| in GLS from BL to 1-3 wk after AC#4. However, the study was underpowered due to small sample size and there was a suggestion of reduced CT with simvastatin. Co-administration of simvastatin and AC was safe and serial echocardiographic strain monitoring was feasible. Further studies are needed to evaluate the cardioprotective effect of statins on strain in BC patients receiving anthracyclines. Citation Format: Smith KL, Griffin JM, Tsai H-L, Leathers M, Hays A, Lu D-Y, Zhang Z, Rosner GL, Russell SD, Connolly RM, Jelovac D, Visvanathan K, Wolff AC, Stearns V, Abraham T. Effect of simvastatin on cardiac strain in breast cancer patients receiving anthracycline therapy [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 P4-16-09.

Background: Breast cancer (BCA) presents with distinct molecular subtypes, each associated with different patterns of relapse, drug sensitivity, and prognosis. Although age at diagnosis is a recognized independent prognostic risk factor, its relative importance among molecular subtypes is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among BCA patients of different immunohistochemical subtypes (LuminalA, LuminalB, Her2, Triple-negative). Methods: We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital from January 2000 - December 2016, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41-60, and > 60 years, and multivariable analysis was performed using Cox regression. To explore age-related differences in gene expression, we identified differentially expressed genes (DEG) between age groups among BCA subtypes in the TCGA dataset. Finally, we identified key driver genes within DEG using a weighted gene co-expression network analysis. Results: Our cohort included 3,524 patients with a median follow-up of 85.1 months. LuminalA breast cancer patients had significantly lower 5-year Disease Free Survival (DFS) and Distant Metastasis-Free Survival (DMFS) in the ≤ 40 year age group compared to the 40-60 year age group (HR=2.69, 95%CI: 1.72 - 4.23 and HR=2.95, 95%CI: 1.78 - 4.90, respectively), while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger predictor of 5- year DFS and 5-year DMFS than tumor grade or proliferative index (Ki67) in LuminalA BCA patients, but not other subtypes. Gene expression data were obtained from 1097 BCA TCGA patients, divided into two groups (≤40y, n=36; >40y, n=455). We identified 374 DEG between ≤40y and >40y LuminalA BCA subsets. The DEG were enriched in 7 pathways, and the WGCNA analysis identified two modules of co-expressed genes. No age group-specific DEG were identified in non-LuminalA subtypes. Conclusion: Age at diagnosis may be an important prognostic factor in LuminalA BCA and may improve risk stratification and personalized therapy. Prospective studies are needed to further evaluate the prognostic value of age in this subset of BCA patients. Citation Format: Liu Z, Sahli Z, Wang Y, Wolff AC, Cope L, Umbricht CB. Young age at diagnosis is associated with worse prognosis in the luminal A breast cancer subtype. A retrospective institutional cohort study [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 P4-08-35.

1564 Background: Enrollment in clinical trials has declined during the COVID-19 pandemic. Simultaneously, breast cancer patients have reported heightened anxiety. We assessed whether breast cancer patients’ anxiety about the pandemic affects their willingness to participate in trials. Methods: English or Spanish-speaking US residents with breast cancer were eligible to complete the online REDCap survey 8/6/21 – 9/30/21. Respondents rated their anxiety about the pandemic on an 11-point scale from 0 (no anxiety) to 10 (worst anxiety possible). Anxiety scores were categorized as no/mild (0-3), moderate (4-6) or severe (7-10). Knowledge about trials was assessed with 11 true/false items and attitudes toward trials with the Attitudes Toward Cancer Trials Scales - Cancer Treatment Subscale (ATCTS-CTS). Respondents rated their willingness to participate in a breast cancer clinical trial before and during the pandemic on 5-point scales from 0 (not at all willing) to 4 (definitely willing). Trial participants were considered “definitely willing.” Change in willingness to participate in trials during the pandemic compared to prior was defined as a binary outcome, "less willing" vs "no less willing." Means were compared via t-test and mean difference was tested via paired t-test. Multivariable logistic regression was used to model the association of anxiety and other factors with being less willing to participate in trials during compared to prior to the pandemic. Results: Among 385 respondents, median age was 52 (range 25-85), 271 (70%) were non-Hispanic White and 202 (53%) had metastatic disease. 154 (40%) received care at academic centers and 37 (10%) were current trial participants. Most rated their anxiety as moderate (43%) or severe (38%). Mean willingness to participate in a trial was lower during compared to prior to the pandemic (2.97 vs 3.10; p < 0.0001). Fifty (13%) respondents were less willing to participate in a trial during the pandemic compared to prior. After controlling for covariates, those with severe anxiety had 5.07 times odds of being less willing to participate during the pandemic compared to prior than those with no/mild anxiety (p = 0.01). For every 1-point increase in ATCTS-CTS score (indicating better attitude toward trials) there was a 3% decrease in the odds of being less willing to participate during the pandemic (p = 0.006). For every 1-point increase in the clinical trials knowledge score (indicating more knowledge) there was a 15% decrease in the odds of being less willing to participate during the pandemic (p = 0.02). Conclusions: Pandemic-related anxiety is common in breast cancer patients and is associated with being less willing to participate in trials during the pandemic compared to prior. Education about trials, including safety modifications implemented during the pandemic, may mitigate anxiety and improve willingness to participate.

521 Background: Clinical trials provide the foundation for evidence-based practices, yet trial participants are often not representative of all patients. Historically, clinical trials involved adding novel agents to standard of care to improve survival. There has been a shift to an individualized approach with testing less intense treatment, yet vulnerable patient groups are at risk for underrepresentation. Little is known about physician perspectives on implementing less intense treatment approaches for patients who are not represented in sufficient number to draw conclusions on subpopulations. Methods: Open-ended, individual qualitative interviews with medical oncologists from different cancer centers exploring their perspectives on trials that test less intense treatment for patients with cancer. Interviews were audio-recorded and transcribed. Four independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. Results: Of the 39 participating physicians, 61.5% felt comfortable extrapolating, 30.8% were hesitant, and 7.7% would not feel comfortable extrapolating trial outcomes to underrepresented populations. One physician noted, “We've been extrapolating for as long as I can remember and certainly that I've been in practice; so we do need to do better there, but extrapolation is only natural with what we have.” Facilitators of comfort included sentiment that “biology is biology”, such that the cancer characteristics were what mattered; the strength of the evidence from the trial overall; inclusion of subset analysis on underrepresented populations; and prior experience making decisions with limited data. Barriers to extrapolation included the potential harm over the patient’s lifetime; concerns about groups that had minimal participants; application specifically to younger patients; and extending findings to racially and ethnically diverse populations. Oncologists highlighted the need for shared decision-making when applying study results to underrepresented populations. They also expressed concerns about study findings being applied to patients who would have been ineligible in the original trials. Universally, broader inclusion in trials testing lowering chemotherapy is desired. Conclusions: The majority (92%) of physicians report that they would extrapolate clinical trial results to patients poorly represented in de-escalation trials, while expressing concerns about applicability to specific subpopulations based on tumor characteristics (e.g. stage, biology) and patient demographics (e.g. age, race). Further work is needed to increase clinical trial representation of diverse populations to safely and effectively optimize treatment for patients with cancer.

Systemic inflammation is believed to contribute to the distant recurrence of breast cancer. We evaluated serum samples obtained at diagnosis from 249 case:control pairs with stage II-III Her2-negative breast cancer with or without subsequent distant recurrence. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations of cytokines with distant recurrence risk. The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). This prospective-retrospective study provides evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk.

Background The Adjuvant Zoledronic Acid (ZA) study in early breast cancer (AZURE) showed correlation between a non-amplified MAF gene in the primary tumor and benefit from adjuvant zoledronic acid (ZA). Adverse ZA outcomes occurred in MAF-amplified patients. NSABP B-34 is a validation study. Methods A retrospective analysis of MAF gene status in NSABP B-34 was performed. Eligible patients were randomly assigned to standard adjuvant systemic treatment plus 3-years oral clodronate (1600mg/daily) or placebo. Tumors were tested for MAF gene amplification, and analyzed for their relationship to clodronate for disease-free survival (DFS) and overall survival (OS) in MAF non-amplified patients. All statistical tests were 2-sided. Results . MAF status was assessed in 2,533 available primary tumor samples from 3,311 patients. Of these, 37 withdrew consent; in 77 samples no tumor was found; 536 assays did not meet quality standards, leaving 1,883 (77.8%) evaluable for MAF assay by fluorescence in situ hybridization (947 from placebo, and 936 from clodronate arms). At 5 years, in MAF non-amplified patients receiving clodronate, DFS improved by 30% (hazard ratio =0.70, 95% confidence interval = 0.51-0.94, P=0.02). OS improved at 5 years (hazard ratio =0.59, 95% confidence interval = 0.37–0.93, P=0.02) remaining statistically significant for clodronate throughout study follow-up. Conversely, adjuvant clodronate in women with MAF-amplified tumors was not associated with benefit, but possible harm in some subgroups. Association between MAF status and menopausal status was not seen. Conclusions Non-amplified MAF showed statistically significant benefits (DFS and OS) with oral clodronate, supporting validation of the AZURE study.

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.

Background As the combination of systemic and targeted chemotherapies is associated with severe adverse side effects and long-term health complications, there is interest in reducing treatment intensity for patients with early stage breast cancer (EBC). Clinical trials are needed to determine if it is feasible to reduce treatment intensity while maintaining 3-year recurrence-free survival of greater than 92%. In order to recruit patients for de-implementation trials, it is important to understand patient perspectives on barriers and facilitators to reducing treatment intensity. Methods We collected qualitative interview data from patients with Stage II-III breast cancer (N=24) and patient advocates (N=16). Interviews explored interest in de-implementation trial participation and identified potential barriers and facilitators to participation. 17 participants were asked about the potential impact of COVID-19 on de-implementation efforts. Interviews were audio-recorded and transcribed, and researchers used qualitative content analysis (NVIVO and Atlas.ti) to code for dominant themes. Results 17 participants (42.5%) expressed interest in participating in a trial of reduced chemotherapy. Barriers to reducing chemotherapy included (1) fear of recurrence and inefficacy, (2) preference for aggressive treatment, (3) disinterest in clinical trials, (4) lack of information about expected outcomes, (5) fear of regret, and (6) having young children. Facilitators included (1) avoiding physical toxicity, (2) understanding the scientific rationale of reducing chemotherapy, (3) confidence in providers, (4) consistent monitoring and the option to increase dosage, (5) fewer financial and logistical challenges, and (6) contributing to scientific knowledge. Of those asked, nearly all participants said they would be more motivated to reduce treatment intensity in the context of Covid-19, primarily in order to avoid exposure to the virus while receiving treatment. Conclusions We recommend framing de-implementation strategies and recruitment to trials in terms of customizing treatment to the individual patient and added benefit—reduced toxicities, higher quality of life during treatment and lower risk of long-term complications—rather than in terms of taking treatments away or doing less than the standard of care. Doctor-patient rapport and provider support will be crucial in this process.

Background:Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC.Methods:We included patients diagnosed with stage I–III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with aPResults:Among all patients with breast cancer treated at these centers, 3,016 fit the inclusion criteria. Training cohort (n=2,112) bivariable analyses identified disease stage, insurance type, age, body mass index, race, and income as being associated with rrTNBC (PP24 months), we found that insurance type and young age remained significant.Conclusions:Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Ductal in-situ carcinoma (DCIS) is a non-invasive proliferation that lacks the ability to metastasize. Over the past four decades, DCIS diagnoses have increased ten-fold, with treatments nearly as aggressive as those for small low-grade invasive breast cancer. In this study, we evaluate the potential of identifying intrinsic imaging phenotype of DCIS using radiomic signatures from breast DCE-MRI. The rationale is that such phenotypes may capture aspects of the heterogeneity of DCIS that can aid in identifying indolent from aggressive disease to better stratify patients for improved disease management. An initial analysis was performed on eighty- two DCIS cases from the ECOG-ACRIN E4112 trial. The Cancer Phenomics Toolkit (CapTK) was used to extract a total of 95 3-D radiomic features from each primary lesion volume in pre-treatment, pre-operative breast DCE-MRI images. Features were first filtered for robustness across the heterogeneous clinical sites of DCE-MRI acquisition and features deemed non-robust (59) were discarded. Dimensionality reduction was performed with the remaining thirty-six features via principle component analysis (PCA). Unsupervised hierarchical clustering of the resulting five principal components (PCs) capturing 85% of the original feature variance was applied. Two significant intrinsic DCIS radiomic phenotypes were identified (p