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Purpose: In contrast to recurrence after initial diagnosis of stage I–III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2− tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

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.

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

Background Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. Patients and Methods We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343 . Results From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor–positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). Conclusion Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.

Background Breast cancer subtypes are associated with distinct metastatic patterns. Whether germline BRCA1 /BRCA2 mutation status is independently associated with central nervous system (CNS) relapse, controlling for tumor subtype, is unknown. Methods Patients who were treated at Dana‐Farber Cancer Institute and diagnosed with a first locoregional recurrence (LRR) or metastasis between 1981 and 2014 were identified using 2 institutional registries: 1) patients treated for recurrent breast cancer and 2) patients who underwent BRCA testing. The frequencies of LRR, sites of metastasis, and breast cancer‐specific survival from LRR or metastasis were calculated, and the factors associated with CNS recurrence were evaluated using multivariable logistic regression models. Results The final study cohort included 30 BRCA1 mutation carriers, 32 BRCA2 mutation carriers, and 270 noncarriers. Most BRCA1 carriers (73%) had triple‐negative breast cancer; whereas most BRCA2 carriers (72%) had hormone receptor‐positive tumors. BRCA1 carriers frequently experienced lung and distant lymph node metastasis, whereas BRCA2 carriers and noncarriers most often experienced bone metastasis. Although CNS disease occurred frequently in both BRCA1 and BRCA2 carriers (53% BRCA1, 50% BRCA2, 25% noncarriers; P, Germline BRCA1 or BRCA2 alterations are associated with a high frequency (≥50%) of brain metastases in patients with locoregionally recurrent or metastatic breast cancer. In multivariable analysis, only BRCA2 mutation (P = .006) was significantly associated with central nervous system metastasis when controlling for breast cancer subtype.

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.

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

Summary Background Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. Methods In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov , number NCT01623349 . Findings Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3–4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Interpretation Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Funding Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.

BACKGROUND The authors conducted a cluster randomized study to determine the effect of an exportable educational intervention for young women with breast cancer (YWI) on improving care. METHODS Sites were randomized 1:1 to the YWI or a contact time control physical activity intervention (PAI) stratified by academic or community site. Up to 15 women aged ≤45 years with newly diagnosed breast cancer were enrolled at each of 14 academic sites and 10 were enrolled at each of 40 community sites. The primary endpoint, attention to fertility, was ascertained by medical record review. Statistical inferences concerning the effect of the intervention used general estimating equations for clustered data. RESULTS A total of 467 patients across 54 sites were enrolled between July 2012 and December 2013. The median age of the patients at the time of diagnosis was 40 years (range, 22-45 years). Attention to fertility by 3 months was observed in 55% of patients in the YWI and 58% of patients in the PAI (P = .88). Rates were found to be strongly correlated with age (P

BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

Background Obesity and inactivity are associated with increased risk of cancer-related and overall mortality in breast cancer, but there are few data in metastatic disease. Methods Cancer and Leukemia Group B 40502 was a randomized trial of first-line taxane-based chemotherapy for patients with metastatic breast cancer. Height and weight were collected at enrollment. After 299 patients enrolled, the study was amended to assess recreational physical activity (PA) at enrollment using the Nurses’ Health Study Exercise Questionnaire. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using stratified Cox modeling (strata included hormone receptor status, prior taxane, bevacizumab use, and treatment arm). All statistical tests were 2-sided. Results A total of 799 patients were enrolled, and at the time of data lock, median follow-up was 60 months. At enrollment, median age was 56.7 years, 73.1% of participants had hormone receptor–positive cancers, 42.6% had obesity, and 47.6% engaged in less than 3 metabolic equivalents of task (MET) hours of PA per week ( Conclusions In a trial of first-line chemotherapy for metastatic breast cancer, rates of obesity and inactivity were high. There was no statistically significant relationship between body mass index and outcomes. More information is needed regarding the relationship between PA and outcomes.

The role of breast magnetic resonance imaging (MRI) in the screening of breast cancer survivors with remaining breast tissue is not well studied. We sought to evaluate the outcomes of screening breast MRI in a cohort of breast cancer survivors. A population of patients with history of stage I-IIIa breast cancer and ≥1 MRI a year or later from diagnosis between 2006-2008 were identified using the National Comprehensive Cancer Network data base from two large Boston-area cancer centers. Patient and disease characteristics were obtained from the data base, and medical records were reviewed to identify the index MRI (first eligible), indications, and two-year outcomes. Overall, 647 patients had breast MRI scans during the study period including 342 eligible patients whose index MRIs were done for breast screening purposes. 47/342 (13.7%) were abnormal, and 3.8% (13/342) underwent biopsy, resulting in the detection of 3 cases of locoregional recurrence or new primary breast cancer (0.9%, 95% CI = 0.2%-2.5%). Of 295 patients with a normal index screening MRI, 12 had a breast cancer recurrence diagnosed within 2 years (4.1% 95%CI = 2.1%-7.0%), and 5 of these recurrences were limited to MRI-screened breast tissue. No statistically significant difference in the rate of 2-year locoregional or distant recurrence was observed between patients with an abnormal screening MRI and those with a normal scan. Adjunct single breast MRI surveillance in a general population of breast cancer survivors one year after diagnosis detected few recurrences, and its effect on short-term outcomes was unclear.

Purpose: We conducted a meta-analysis of randomised trials evaluating pathological complete response (pCR) and surgical outcomes after neoadjuvant systemic therapy (NST) in patients with early breast cancer (EBC). Patients and methods: The primary outcome was breast-conserving surgery (BCT) rate. Secondary outcomes were pCR rate and association to BCT. Meta-analyses were performed using random effects models that use inverse-variance weighting for each treatment arm based on evaluable patients. Point estimates are reported with 95% confidence interval (CI), and p < 0.05 was considered statistically significant. Results: Thirty-six studies were identified (N = 12,311 patients). We selected for the analysis 16 of 36 studies reporting both pCR and BCT for at least one treatment arm. Arms per study ranged from one to six; 42 independent units were available to evaluate the association between pCR and BCT. BCT rate ranged 5-76% across arms with an average BCT of 57% (95% CI 52-62%). Significant heterogeneity was observed among the trials (Cochrane Q = 787, p < 0.001, I2 = 97%). In the meta-regression model, BCT rates were not significantly associated with year of first patient-in (p = 0.89), grade (p = 0.93) and hormone-receptor status (p = 0.39). Clinical N-stage (p = 0.01) and human epidermal growth factor receptor (HER2) status (p = 0.03) were significantly associated with BCT. pCR rate ranged 3-60% across studies. The average pCR across all study arms was 24% (95% CI 19-29%). No association was observed between pCR rate in a study arm and the resulting BCT rate in a univariate model (p = 0.34) nor after adjusting for HER2 and clinical nodal status (p = 0.82). In the subset of 14 multi-arm studies, no significant association was seen between the differences in pCR and BCT between treatment arms (p = 0.27). Conclusions: pCR does not increase BCT in patients receiving NST for EBC.

The after mapping of the axilla: radiotherapy or surgery (AMAROS) trial concluded that for patients with cT1-2 N0 breast cancer and one or two positive sentinel lymph nodes (SLNs), axillary radiotherapy (AxRT) provides equivalent locoregional control and a lower incidence of lymphedema compared with axillary lymph node dissection (ALND). The study prospectively assessed how often ALND could be replaced by AxRT in a consecutive cohort of patients undergoing mastectomy for cT1-2 N0 breast cancer. In November 2015, our multidisciplinary group agreed to omit routine intraoperative SLN evaluation for cT1-2 N0 patients undergoing upfront mastectomy and potentially eligible for postmastectomy radiation therapy (PMRT), including those 60 years of age or younger and those older than 60 years with high-risk features. Patients with one or two positive SLNs on final pathology were reviewed to determine whether PMRT including the full axilla was an appropriate alternative to ALND. From November 2015 to December 2016, 154 patients met the study criteria, and 114 (74%) formed the final study cohort. Intraoperative SLN evaluation was omitted for 76 patients (67%). Of these patients, 20 (26%) had one or two positive SLNs, and 14 of these patients received PMRT + AxRT as an alternative to ALND. Three patients returned for ALND, and three patients were observed. On univariate analysis, tumor size, LVI, number of positive lymph nodes, and receipt of chemotherapy were associated with receipt of PMRT. For the majority of patients with one or two positive SLNs, ALND was avoided in favor of PMRT + AxRT. With appropriate multidisciplinary strategies, intraoperative evaluation of the SLN and immediate ALND can be avoided for patients meeting the AMAROS criteria and eligible for PMRT.

Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2–5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1−ERBB2−, 48% ESR1+ERBB2−, and 27% ERBB2+. Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression “fingerprints” were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486–99. ©2018 AACR.

Background Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort. Methods Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer-specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR)-positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables. Results Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged ≥85 years. Regardless of stage of disease within the HR-positive and HR-negative cohorts, patients aged ≥75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68-2.09] and hazard ratio for those aged ≥85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged ≥70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple-negative disease. Conclusions Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. Cancer 2018;124:2184-91. © 2018 American Cancer Society.

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

Background: CALGB 40502/NCCTG N063H (Alliance) compared weekly NP or Ix to P; most patients received bevacizumab. Ix was inferior to P, and NP was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms compared to P (Rugo et al, JCO 2015). We report long-term follow-up (FU) of this trial with an unplanned subset analysis in hormone receptor positive (HR+) and triple negative (TNBC) breast cancer. Methods: Patients were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 week (wk) on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all patients, but became optional in 3/2011 and was added to stratification. The primary endpoint was progression-free survival (PFS); secondary endpoints included safety and overall survival (OS). With a target N=900 patients, the study was powered to detect a hazard ratio of 1.36 (median PFS 10 vs 13.6 months). Eligibility included no prior chemotherapy for MBC, >12 mo from adjuvant P and measurable disease. Results: 799 patients were randomized between 11/08 and11/11 (283 to P, 271 to NP, 245 to Ix); 98% received bevacizumab. 68% (546) had HR+ disease, 25% (201) had TNBC. Median FU is 5 years. Median PFS is unchanged at 10.8, 9.2 and 7.4 mo for P, NP and Ix with hazard ratios (95% CIs) of 1.13 (0.94-1.34) and 1.44 (1.2-1.72) for NP and Ix to P, respectively. Median OS was 27.1, 24.2 and 23.6 months for P, NP and Ix with hazard ratios of 1.10 (0.91-1.34) and 1.3 (1.07-1.57) for NP and Ix to P, respectively. The effects of NP vs P on PFS and OS were significantly modified by subtype (interaction p=0.0018 and 0.0073), whereas Ix vs P was unchanged (interaction p's > 0.9, Table). More patients discontinued treatment due to adverse events in the experimental arms (14 vs 27 vs 23% for P, NP and Ix). Table P (mo)NP (mo)NP to P; HR (95% CI)Ix (mo)Ix to P, HR (95% CI)TNBC, PFS6.47.40.79 (0.55-1.12)15.61.39 (0.99-1.96)3HR+, PFS12.29.61.29 (1.04-1.59)181.5 (1.21-1.86)3TNBC, OS15.3210.74 (0.51-1.07)215.11.28(0.9-1.82)4HR+, OS33.226.61.25 (0.99-1.58)225.41.35(1.07-1.714Interaction tests: 1. p=0.0018; 2. p=0.0073; 3. p=0.96; 4. p=0.92 mo: months; HR: hazard ratio·· Conclusion: In patients with chemotherapy-naive MBC, Ix was inferior to P for PFS, and P was better tolerated than either NP or Ix. In this retrospective subset analysis, Ix and NP were inferior to P in HR+ disease, with a suggestion of improved PFS and OS with NP in patients with TNBC. Further investigation is required to explain and validate the subtype specificity seen in this exploratory analysis. Support: U10CA180820, U10CA180821, U10CA180882, U10CA180888. ClinicalTrials.gov Identifier: NCT00785291 Citation Format: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss A, Huebner L, Mayer EL, Naughton M, Layman RM, Carey LA, Somer RA, Toppmeyer D, Velasco M, Perez EA, Hudis CA, Winer E. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-06.

Prior studies have identified shortcomings in the quality of care for early-stage breast cancer. Guidelines recommend systemic therapy for metastatic breast cancer (MBC), but few studies have examined guideline concordance for these patients. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients aged ≥ 66 diagnosed in 2010–2011 with de novo MBC who were continuously enrolled in fee-for-service Medicare. We described initial care (within 6 months of diagnosis) for hormone receptor (HR)-positive/human epidermal receptor-2 (HER2)-negative, HER2-positive, and triple-negative (TN) tumors. We identified factors independently associated with receiving no initial systemic therapy, and compared hospice and hospital utilization for treated versus untreated patients. Among 446 patients, 65% were HR-positive, 21% were HER2-positive, and 14% were TN. Most patients (76.9%) received initial systemic treatment. Among treated HR-positive patients, 15% received chemotherapy as initial treatment; among treated HER2-positive patients, 34% did not receive HER2-targeted initial therapy. Factors independently associated with receiving no initial systemic therapy included older age (ORage continuous/year = 1.08, 95% CI 1.04–1.11), being not married (ORnot married vs. married = 2.87, 95% CI 1.42–5.81), and subtype (ORTN vs. HR+ = 4.95, 95% CI 2.53–9.71). Of patients who did not receive initial systemic therapy, 41.1% did not receive hospice services. In this population-based MBC cohort, almost one quarter did not receive initial systemic therapy and a substantial proportion of treated patients did not receive guideline-concordant first-line therapy. Further research should explore underuse of chemotherapy and HER2-targeted therapies, investigate whether patterns of care are consistent with patient preferences, and identify opportunities to optimize hospice utilization for patients not receiving treatment.

Excess body weight is a poor prognostic factor in women with early breast cancer, but the effect of weight loss on the risk of breast cancer recurrence and mortality in women who are overweight or obese at the time of breast cancer diagnosis has not been evaluated. The Alliance for Clinical Trials in Oncology Breast Cancer Weight Loss trial, also known as A011401, is testing the impact of a telephone-based weight loss program on invasive disease-free survival in 3136 women with a body mass index ≥27 kg/m2 who have recently been diagnosed with stage II-III, HER-2 negative breast cancer. Secondary outcomes of the trial include the impact of the weight loss intervention on overall survival, body weight, physical activity, dietary intakes, incidence of comorbidities, serum biomarkers and patient reported outcomes. Participants are randomized 1:1 to a 2-year, telephone-based weight loss intervention or to an education control group. The intervention is delivered through 42 telephone calls, delivered by health coaches based at the Dana-Farber Cancer Institute. Calls are supplemented by an intervention workbook, as well as a number of tools to help facilitate weight loss. Intervention goals include loss of 10% of baseline body weight, achieved through caloric restriction and increased physical activity. This large-scale study testing the impact of purposeful weight loss after cancer diagnosis on the risk of breast cancer recurrence and mortality has the potential to make weight loss programs a standard part of breast cancer treatment.

A diagnosis of lobular carcinoma in situ (LCIS) is associated with an increased risk of developing breast cancer, although little data exist on long-term patient outcomes, including those who develop subsequent breast malignancies. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women with a histological diagnosis of LCIS between 1983 and 2014. The incidence and clinicopathologic features of subsequent malignancies were then examined, and the Kaplan–Meier method and multivariable Cox PH regression used to obtain breast cancer-specific survival (BCSS) estimates and associated hazard ratios. Overall, 19,462 women swith a mean age at LCIS diagnosis of 53.7 years, and a 10- and 20-year cumulative incidence of subsequent breast malignancy of 11.3% [95% confidence interval (CI) 10.7–11.9%] and 19.8% (95% CI 18.8–20.9) met the eligibility criteria. At a median follow-up of 8.1 years (range 0–30.9) a total of 1837 primary breast cancers were diagnosed, of which 55.2% were diagnosed in the ipsilateral breast. Most breast cancers were of low/intermediate grade, hormone receptor-positive, and diagnosed in early stages. Of subsequent malignancies, invasive ductal carcinoma (IDC) distributed equally across both breasts, whereas invasive lobular carcinoma (ILC) was more likely to present in the ipsilateral breast (69.0% ILC vs. 49.2% IDC; p

Background Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germlineBRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Background: In triple-negative breast cancers (TNBC), high proliferation is associated with greater chemosensitivity but, paradoxically, also associated with poor prognosis. We hypothesized that this subset of TNBC has distinct transcriptional features that contribute to poor prognosis. Approach: To evaluate transcriptional signatures associated with this 'proliferation paradox,' we identified 17 study cohorts of TNBC treated with neoadjuvant chemotherapy (NAC) that reported receptor status, pathologic response, and had expression data from biopsies obtained prior to NAC (n=446). In 6 studies, distant metastasis-free survival (DMFS) data was available for 235 patients with a median follow-up of 31.2 months. We calculated scores for 135 published gene expression signatures for each tumor and evaluated the association with response to chemotherapy and DMFS. Results: Using recursive partitioning to develop a model of response using a training set (n=340), six of the 135 expression signatures stratify primary tumors into four groups based on signatures of proliferation, BRCA1 mutation, immune, luminal, Ras, and PI3K phenotypes (Table 1.). Response to NAC ranged from 11% to 61% pCR/RCB-I and results were highly concordant when applied to a validation set (n = 106, p = 0.006). The group that was highly proliferative but chemoresistant ('resistant' group) had a distinct transcriptional profile, including lower 'BRCA-ness' and DNA damage expression signatures with higher Ras and stem cell signatures. The 'resistant' group had the poorest DMFS (HR 2.48 [1.52-4.06]; log-rank p=0.002) and this poor survival was validated among chemotherapy-treated TNBCs in a separate dataset, METABRIC. Analyses of only patients with residual disease after NAC demonstrated that the 'resistant' group remained poorest prognosis, with median DMFS of only 31 months from diagnosis. Conclusions: Using a novel approach to categorize primary TNBC tumors based on six signatures, we can effectively distinguish subgroups with higher versus lower pCR rates. One specific group demonstrated high proliferation but low response to chemotherapy and particularly poor survival. This group demonstrates expression signatures implicating DNA damage repair, stemness, and Ras pathway activity as potential mediators of the phenotype. We identify specific molecular characteristics for investigation in patients within a poor prognosis subgroup of TNBC. Table 1. Proportion Pathologic Complete Response or RCB-I and Survival Low ProlifHigh Prolif / ResistantHigh Prolif / SensitiveHigh ImmuneSignature StratificationLow GGI + High LuminalHigh GGI + Low BRCA1mut or High RasHigh GGI + High PI3K or Low RasHigh TNBC ImmunepCR/RCB-I rate: Training Set11/105 (10.5%)26/127 (20.5%)42/81 (51.9%)16/27 (59.3%)pCR/RCB-I rate: Validation Set3/23 (13.0%)11/45 (24.4%)13/29 (44.8%)6/9 (66.7%)pCR/RCB-I rate: TOTAL14/128 (10.9%)37/172 (21.5%)55/110 (50.0%)22/36 (61.1%)Overall Survival (n=235)Hazard Ratio (95% CI)1.62 (0.99-2.64)2.48 (1.52-4.06)(ref.)0.47 (0.29-0.77)Signatures GGI (Sotiriou, JNCI 2006); Luminal (Lim, Nat Med 2009); BRCA1 mutation (van't Veer, Nature 2002); Ras (Pratilas, PNAS 2009); PI3K (Gatza, PNAS 2010), TNBC Immune (Lehmann, JCI 2011) Citation Format: Stover DG, Selfors LM, Winer EP, Partridge AH, Barry WT. Integrated transcriptional analysis of the triple negative 'proliferation paradox': High proliferation, chemosensitivity, and poor prognosis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-05.

Purpose: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer. Experimental Design: Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer–related gene expression signatures were calculated for each tumor. Results: Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish “proliferation-associated” from “proliferation-independent” signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER+/HER2− and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2− breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and “stemness” phenotypes. Conclusions: Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2− breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER+/HER2− breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. Clin Cancer Res; 22(24); 6039–50. ©2016 AACR.

Background Young women with breast cancer tend to report lower quality of life and higher levels of stress than older women with breast cancer, and this may have implications for other psychosocial factors including finances. We sought to determine if stress, anxiety, and depression at diagnosis were associated with changes in household income over 12-months in young women with breast cancer in the United States. Methods This study was a prospective, longitudinal cohort study comprised of women enrolled in the Young and Strong trial. Of the 467 women aged 18–45 newly diagnosed with early-stage breast cancer enrolled in the Young and Strong trial from 2012 to 2013, 356 (76%) answered income questions. Change in household income from baseline to 12 months was assessed and women were categorized as having lost, gained, maintained the same household income Results Although most women maintained household income ≥$100,000 (37.1%) or the same household income Conclusions Baseline stress, anxiety, and depression were not associated with household income changes for young women with breast cancer. However, lower baseline household income was associated with losing household income. Some young survivors encounter financial and insurance problems in the first year after diagnosis, and further support for these women should be considered. Trial registration Clinicaltrials.gov, NCT01647607; date registered: July 23, 2012.

To analyze the efficacy and tolerability of cabozantinib—a small molecule inhibitor of MET and VEGFR2—alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1–9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. Clinicaltrial.gov registration: NCT02260531.

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

Background The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer. Patients and methods Eligible patients with HR+/HER2− stage II–III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. Results Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. Conclusion Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. Clinicaltrials.gov registration NCT02040857.

Purpose: Hormone receptor–positive/HER2-negative (HR+/HER2−) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR+/HER2− breast tumors. Experimental Design: HR+/HER2− breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8+ cells, CD68+ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: Ninety-six patients were analyzed from two cohorts (n = 55, Dana-Farber cohort; n = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N = 302). In paired pre-/postchemotherapy samples, sTIL and CD8+ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy. Conclusions: The immune microenvironment of HR+/HER2− tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.

This study evaluates the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with metastatic triple‐negative breast cancer (mTNBC). Cabozantinib showed encouraging safety and efficacy signals but did not meet the prespecified primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and soluble MET should be further evaluated as a potential biomarker of response., Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3‐week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression‐free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar‐plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF‐D, stromal cell‐derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p

Adjuvant trastuzumab for human epidermal growth factor receptor-2 (HER2)-positive breast cancer is highly efficacious regardless of age. Recent data suggested that many older patients with HER2-positive disease do not receive adjuvant trastuzumab. Nevertheless, some of this 'under-treatment' may be clinically appropriate. We used Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify patients aged ≥ 66 with stage ≥ Ib-III, HER2-positive breast cancer diagnosed during 2010-2011 (HER2 status available) who did not have a history of congestive heart failure. We described all systemic treatments received and sociodemographic and clinical characteristics associated with treatment patterns. Among 770 women 44.4 % did not receive trastuzumab, including 21.8 % who received endocrine therapy only, 6.3 % who received chemotherapy (±endocrine therapy) and 16.2 % who did not receive any systemic therapy. In addition to age and grade, race was strongly associated with non-use of trastuzumab (64.4 % of Non-Hispanic blacks vs. 43.6 % of whites did not receive trastuzumab, adjusted ORNon-Hispanic black vs. white = 3.14, 95 %CI = 1.38-7.17), and many patients with stage III disease did not receive trastuzumab. Further, 16.2 % of patients did not receive any systemic treatment and this occurred more frequently for black patients. Over 40 % of older patients with indication to receive adjuvant trastuzumab did not receive it and nearly 20 % of these patients did not receive any other treatment. Although treatment omission may be appropriate in some cases, we observed concerning differences in trastuzumab receipt, particularly for black women. Strategies to optimize care for older patients and to eliminate treatment disparities are urgently needed.

Few contemporary data are available that compare incidence and survival of metastatic breast cancer between ductal and lobular carcinomas. Using the Surveillance, Epidemiology, and End Results-9 registries, we identified 10,639 patients with de novo metastatic breast cancer diagnosed from 1990 to 2011. Annual age-adjusted incidence rates and annual percent changes (APCs) were analyzed. Multivariable Cox regression models were used to investigate the impact of year of diagnosis and histology on overall survival. 9250 (86.9 %) patients had ductal and 1389 (13.1 %) had lobular carcinomas. Metastatic breast cancer incidence increased slightly over time for ductal (APC = +1.7, 95 % confidence interval (CI) = +1.0 to +2.4) and lobular carcinomas (APC = +3.0, 95 % CI = +1.8 to +4.3). Median overall survival was 22 months among the whole cohort. More recent year of diagnosis was associated with better overall survival only for patients with ductal carcinomas (interaction p value = 0.006), with an adjusted hazard ratio of death for every five-year increment in the date of diagnosis of 0.93 (95 % CI = 0.91-0.95) among ductal carcinomas, compared with 1.05 (95 % CI = 0.95-1.10) among lobular carcinomas. Overall survival was longer for lobular versus ductal carcinomas (28 versus 21 months, respectively; adjusted hazard ratio of death = 0.93, 95 % CI = 0.87-0.99), but the magnitude of this effect was attenuated among the cohort restricted to hormone receptor-positive tumors. In this population-based analysis, incidence rates of metastatic breast cancer at presentation increased slightly over time for both histologies, and particularly for lobular tumors. A modest improvement in metastatic breast cancer median overall survival was observed, but was apparently limited to ductal carcinomas.

The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case–control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67+ cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12–48.0]. Conversely, the frequency of ER+ or p27+ cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER+: OR = 0.70, 95% CI, 0.33–1.50; p27+: OR = 0.89, 95% CI, 0.45–1.75). Notably, high Ki67+/low p27+ and high Ki67+/low ER+ cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67+/low p27+ and low Ki67+/low ER+ cell frequencies, respectively, among premenopausal women (Ki67hi/p27lo: OR = 5.08, 95% CI, 1.43–18.1; Ki67hi/ERlo: OR = 4.68, 95% CI, 1.63–13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926–34. ©2016 AACR.

Background: Survival for metastatic breast cancer (MBC) patients (pts) has modestly improved over time. Until the early 2000's, incidence rates for invasive lobular carcinoma (ILC) had steadily risen, in contrast to the stable rates observed for invasive ductal carcinoma (IDC). Historically, ILC was deemed to have a more favorable prognosis than IDC. Nevertheless, data on recent time trends in incidence and survival of lobular vs. ductal histology among newly diagnosed MBC pts are limited. Pts and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 9 registries, we included 10,767 pts diagnosed with de novo lobular or ductal MBC from 1990-2011, and followed through 2012. Time trends in annual age-adjusted incidence rates were analyzed, stratified by histology. Multivariable Cox regression models were fit to investigate the association of year of diagnosis and overall survival (OS) by stratum, adjusting for features presented in Table 1. We examined interactions between year of diagnosis and histology. In sensitivity analyses, we modeled year of diagnosis as categorical, and restricted the cohort to hormone-receptor positive pts. Table 1IDC N= 9,376 (87%)ILC N= 1,391 (13%)Cohort characteristics%Age, yearsƚ Results: 9,376 (87%) pts had IDC and 1,391 (13%) had ILC. Overall, we found a 1.4 fold increase in incidence rates for de novo MBC over the study period, (with a 1.3- and 2.6-fold increase for IDC and ILC, respectively). OS improved over the study period for the overall cohort (Hazard ratio (HR) of death=0.99; 95% confidence interval (CI)=0.98-0.99; 1% decrease/year; 5% decrease/5 years; p=.0059 for the interaction year of diagnosis-histology on OS). ILC pts had better outcomes than IDC pts (median OS=28 vs. 21 months; adjusted HR of death= 0.93; 95%CI=0.87-0.99). For IDC pts, we found a statistically significant improvement in OS over time (HR of death=0.98; 95%CI=0.98-0.99; 2% decrease/year; 6% decrease/5 years). However, we observed no significant change in survival outcomes for ILC pts (HR of death=1.01; 95%CI=0.99-1.02) (Table 1). Results from sensitivity analyses were similar. Conclusions: From 1990-2011, incidence rates for de novo MBC increased. In this cohort, ILC pts had a better prognosis than IDC pts. Nevertheless, although we found an expected overall improvement in OS for MBC pts, this effect was restricted to IDC pts, with no significant improvement among ILC pts. Dedicated studies are warranted to understand whether our results can be confirmed in other datasets and to investigate the reasons driving this discrepancy, such as the impact of patterns of care, new drug approvals, and tumor molecular subtype. Citation Format: Di Meglio A, Freedman RA, Lin NU, Barry WT, Metzger-Filho O, Keating NL, Winer EP, Vaz-Luis I. Time trends in incidence rates and survival for women with de novo metastatic lobular vs. ductal carcinoma, a population-based study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-08.

Background: In general, radiotherapy (RT) follows breast-conserving surgery (BCS) and remains the standard of care for the surgical management of both invasive carcinoma and ductal carcinoma in situ (DCIS). Although it is associated with better local control, the magnitude of survival benefit conferred by RT for DCIS has not yet been established. We sought to evaluate whether a survival benefit exists with the addition of RT for patients with DCIS and to validate a patient prognostic score to predict survival benefit. Methods: We performed a retrospective longitudinal cohort study by using the Surveillance Epidemiology and End Results database (SEER 17). Between 1988-2007, we identified 32,144 eligible patients who underwent BCS for DCIS. Using age, year of diagnosis, race, tumor size, hormone receptor status, tumor grade, marital status and SEER region, we calculated propensity score weights to balance clinicopathologic factors between patients receiving only surgery and those receiving surgery and RT. This cohort was divided into seven groups according to the previously validated patient prognostic score proposed by Smith et al. Breast cancer mortality (BCM) was assessed using a log-rank test and a multivariable Cox proportional hazards model. Results: Of 32,144 cases of DCIS, 20,329 cases (63%) were treated with RT (+RT group) and 11,815 cases (37%) were treated with surgery alone (-RT group). There were 304 breast cancer-specific deaths observed over the follow-up period (median 96 months). The weighted cumulative incidence of BCM at ten-years was 1.8% for the +RT group compared to 2.1% for the -RT group (p= 0.003). The effect of RT on survival differed by nuclear grade (p= 0.007), age (p= 0.004), and tumor size (p=0.02). We found that the survival benefit for the +RT group was significantly greater than for the –RT group in subgroups of patients with higher nuclear grade, younger age, and larger tumor size, whereas a statistical reduction of BCM with RT was not observed among patients without these prognostic factors. Moreover, the magnitude of survival benefit was significantly correlated with the patient prognostic score [p Conclusion: In this population-based cohort study, the patient prognostic score for DCIS accurately estimated the magnitude of survival benefit offered by radiotherapy after BCS, suggesting that decisions for RT could be tailored based on prognostic score and patient preference. Limitations of this study include unmeasured confounders such as a lack of information about patients' comorbidities, margin status and endocrine therapy, and further external validation is needed to confirm our results. Patient Prognostic Score and Hazard Ratio (HR) Comparing Mortality between Radiotherapy Group and non-Radiotherapy GroupPatient Prognostic ScoreNumber of patients in -RT groupNumber of patients in +RT groupWeighted HR of BCM95% CIWeighted HR of OM95% CI078213881.20.67 - 2.10.910.76 - 1.11267744801.00.70 - 1.50.880.78 - 0.992410570800.690.51 - 0.940.710.63 - 0.793304854170.730.48 - 1.10.680.58 - 0.81496517010.310.16 - 0.580.420.30 - 0.5852232480.290.09 - 0.910.430.21 - 0.9161515N.A. N.A. Abbreviation: RT, Radiotherapy; BCM, Breast Cancer Mortality; OM, Overall Mortality: N.A., not available Citation Format: Sagara Y, Freedman RA, Vaz-Luis I, Mallory MA, Wong S, Aydogan F, DeSantis S, Barry WT, Golshan M. Patient prognostic score and survival benefit offered by radiotherapy for ductal carcinoma in situ. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-02.

Background The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. Materials and methods In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. Results Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). Conclusion IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. Implications for practice This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.

Background. Recent trials have demonstrated that axillary observation or axillary radiation therapy (AxRT) is equivalent to axillary node dissection (ALND) for patients with one or two positive sentinel lymph nodes (SLNs). These strategies have been widely adopted for patients having breast conservation. This report demonstrates the potential impact of the AMAROS trial on axillary therapy in a retrospective cohort of mastectomy patients. Methods. Patients undergoing primary mastectomy for cT1-2N0 breast cancer who had one or two positive SLNs were identified from institutional databases (2005-2015). Locoregional management strategies were evaluated, and variables predictive of the use of postmastectomy radiation therapy (PMRT) were identified. Results. Among 2594 mastectomies, 193 (7%) met the AMAROS eligibility criteria. The median patient age was 50 years (range 22-83 years). Locoregional treatment consisted of ALND + PMRT for 102 patients (53%), ALND alone for 66 patients (34%), PMRT alone for 11 patients (6%), and observation for 14 patients (7%). Overall, 59 ALND patients (35%) had additional positive nodes. In the multivariate analysis, age younger than 50 years (odds ratio [OR] 3.55; 95% confidence interval [CI] 1.57-8.45), lymphovascular invasion (LVI) (OR 5.78; 95% CI 2.53-4.78), macrometastases (OR 3.99; 95% CI 1.54-10.97), and extracapsular extension (OR 11.66; 95% CI 2.55-88.34) were associated with receipt of PMRT. Conclusion. In this cohort of AMAROS-eligible patients, 168 (87%) underwent ALND, 102 (61%) of whom also received PMRT, suggesting that AxRT could have been used instead of ALND for a significant number of patients. Preoperative factors associated with the receipt of PMRT, such as young age and LVI, may be useful for defining a multidisciplinary decision-making framework for axillary management in this population.

Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

A significant proportion of triple negative breast cancers (TNBC) carry defects in DNA repair including Homologous Recombination (HR) defects and are sensitive to therapies that target these pathways. Several clinical trials have demonstrated improvement in pathologic response with the addition of platinum to standard of care neoadjuvant regimens but at a cost of increased toxicities. Recently three DNA based metrics (LOH, Abkevich et al. 2012 Br J Cancer; TAI, Birkbak et al. 2012 Cancer Discov; LST, Popava et al. 2012 Cancer Res) have been developed, shown to be highly associated with BRCA1/2 mutation status, and found to predict sensitivity to platinum based chemotherapy in TNBC. The HRD Score was defined as the sum of LOH, TAI, and LST measurements, and a threshold separating tumors with high and low HRD Scores was established. This study assesses the association of HRD Score with response to cisplatin neoadjuvant chemotherapy in patients with TNBC. A clinical test that identifies tumors with defects in HR may distinguish those patients more likely to benefit from the addition of platinum. Methods: Archival tumor samples were obtained from 74 patients with TNBC from 2 separate clinical trials conducted at DFHCC under IRB approved protocols. One trial enrolled 28 patients who received neoadjuvant cisplatin monotherapy (Silver et al., 2010 J Clin Oncol). The second trial enrolled 51 patients who received cisplatin and bevacizumab chemotherapy (Ryan, et al.,2009 J Clin Oncol). HRD Score and tumor BRCA1/2 mutation status were determined. BRCA1/2 deficiency was defined as the presence of BRCA1/2 mutation with loss of the second allele in the tumor. Response was categorized by the residual cancer burden (RCB) score with responders defined as RCB0 or 1, and non-responders as RBC2 or 3. A second measure of response, pathologic complete response (pCR), was defined as RCB0 and non-responders as RCB1,2 or 3. Logistic regression was used to evaluate HRD Score in combination with BRCA1/2 deficiency as a predictor of response to neoadjuvant therapy. All analysis was conducted according to a pre-specified Statistical Analysis Plan. Results: As of May 29, 2014 41 samples have been processed. Seven carried deleterious mutations in BRCA1/2 (17%). Thirty-three of the tumors produced SNP data of sufficient quality for HRD score calculation. HRD scores in the passing samples ranged from 7 – 74, with an average score of 45. The HRD scores observed in BRCA1/2 mutation carriers (n=6) ranged from 43 – 57 with an average HRD score of 55. We anticipate that all molecular data will be generated by July 1, 2014. Correlation with pCR and RCB0/1 will be assessed. Conclusions: The LOH, TAI, and LST metrics have been shown in previous studies to predict response to platinum-based neoadjuvant chemotherapy in patients with TNBC. This study will be a validation of LOH, TAI and LST in the form of a combined score, and will demonstrate that HRD Score can be used as a tool to identify patients with breast tumors with underlying HR deficiency who may benefit from platinum therapy. Citation Format: Andrea L Richardson, Daniel P Silver, Zoltan Szallasi, Nicolai J Birkbak, Zhigang C Wang, J Dirk Iglehart, Erica L Mayer, Eric P Winer, Nadine M Tung, Paula D Ryan, Steven J Isakoff, William T Barry, April Greene-Collozi, Alexander Gutin, Julia Reid, Chris Neff, Joshua Jones, Kirsten Timms, Anne-Renee Hartman, Judy E Garber. Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-11.

Background: Recent consensus guideline on margins for breast conserving surgery recommends the use of no ink on tumor as the standard for an adequate margin. Current recommendation extends to invasive lobular carcinoma (ILC), however the data in this subset is limited by small numbers. In the present analysis we sought to evaluate the influence of margin status on outcomes in ILC and mixed tumors. Methods: We performed retrospective cohort study and reviewed 809 eligible patients diagnosed with ILC (337 with pure ILC; 472 with mixed ILC) with Stage I –III treated at Dana Farber/Brigham and Women’s Cancer Center (DFBWCC) between May 1997 and Dec 2007. Clinico-pathologic data was extracted following the Clinical Research Information Systems (CRIS) Database procedures and manually reviewed to confirm inclusion and details of margin status. Margin status was defined using the last ASCO/ASTRO/SSA consensus guidelines criteria. Analysis results were considered to be statistically significant when the two-tailed p-value was Results: Breast conservation was performed in 399 patients (49%). Margin status at the initial attempt for breast conservation was defined as follows: 180 (45%) negative, 64 (16%) positive, 71 (18%) ≤ 1mm margin, and 84 (21%) close margins (> 1 and < 3 mm). Following initial lumpectomy, 102 (25%) patients underwent additional surgery (96 re-excisions and 6 mastectomies) and residual invasive disease was found in 40 patients. Whole-breast radiation therapy was performed in 376 patients (96%). In multivariate models adjusted for classic clinico-pathologic factors, tumor size (HR= 1.8 95% CI 1.0 to 3.3, p=0.05), multifocality (HR= 2.0 95% CI 1.1 to 3.6, p= 0.02) and ILC subtype (HR= 2.0 95% CI 1.0 to 3.7, p=0.04) were correlated with positive margins, while year of diagnosis, age and pre-surgical MRI findings were not statistically significant. With 72 months median follow-up, 12 ipsilateral breast cancers (3.1%), 5 other locoregional (1.2%) and 15 distant (3.8%) recurrences were observed after definitive breast conserving therapy. The incidence of locoregional recurrence (LRR) was 4.3% and similar for ILC and mixed ILC (p=0.76). In univariate analysis positive surgical margin was associated with LRR (HR=5.1, p= 0.03) and disease-free survival (DFS) (HR=8.9, p≤ .001), but due to limited number of cases and events this could not be adjusted for other clinico-pathologic prognostic factors in a mulitvariate model. Close surgical margins, margins within 1mm and multifocality were not associated with increased LRR or worse DFS. Re-excision did not impact on DFS for patients with close margin (p= 0.57) and within 1 mm margin (p= 0.85). By contrast, significant improvement of DFS following re-excision was observed in patients with positive margin (p= 0.01). Conclusions: Following lumpectomy, local recurrence rates for ILC patients with close surgical margin and ≤ 1mm margin are low and equivalent to those in patients with negative margins. This study supports the validity of using no ink on tumor as the standard for an adequate margin for patients diagnosed with pure or mixed ILC treated with multimodality therapy. Citation Format: Yasuaki Sagara, William T Barry, Ines Vaz-Luis, Fatih Aydogan, Jane E Brock, Eric P Winer, Mehra Golshan, Otto Metzger-Filho. Effect of margin width on local recurrence in invasive lobular carcinoma treated with multimodality therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-16-01.

Background: In CALGB 40601, the HER2-Enriched (HER2-E) molecular subtype had significantly higher pathologic complete response (pCR) rates regardless of treatment arm (single HER2-targeting with T+L or T+H, dual targeting with T+H+L) (Carey et al, ASCO 2014). A TP53 mutation gene expression signature was significant in a multivariable analysis as were treatment, molecular subtype, proliferation, and an immune cell genomic signature. Mutational analysis is now available for this sample set. Methods: 265 of 305 enrolled patients (pts) had RNA sequencing (RNAseq) of pre-treatment biospecimens; 181/265 had whole exome sequencing (WES) available from tumor and matched normal blood. Somatic mutations were detected by the program UNCeqR, which integrates WES and RNAseq. We examined the association of mutations with in-breast pCR, molecular subtypes, and gene expression signatures. Results: In this subset, there were 57 HER2-E, 58 Luminal A, 51 Luminal B, 9 Basal-like, 4 Normal-like, and 2 Claudin-low. The pCR rate was 45% (51% THL, 47% TH and 34% TL), consistent with the entire study population. TP53 was the most frequently mutated gene (56%); frequency varied by molecular subtype (Fisher p Conclusions: TP53 mutation is a frequent, clinically important event in HER2-positive disease and predicts pCR to chemotherapy plus HER2-targeting. Frequency and type of mutation was dependent on molecular subtype within this clinically HER2-positive cohort. Ongoing analyses are comparing WES data between pre- and post-treatment samples as well as investigating copy number and clonality. This research is supported in part by funds from GlaxoSmithKline and grants from the Breast Cancer Research Foundation. Citation Format: Katherine A Hoadley, William T Barry, Brandelyn N Pitcher, Joel S Parker, Matthew D Wilkerson, William Irvin Jr, Norah Lynn Henry, Sara M Tolaney, Chau Dang, Ian E Krop, Donald A Berry, Elaine R Mardis, Charles M Perou, Eric P Winer, Clifford A Hudis, Lisa A Carey. Mutational analysis of CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-06.

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha=0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio=1.20; 95% confidence interval=0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (PP=0.44). Proliferation and ROR-PT scores were prognostic for RFS (both PP=0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Breast-conserving surgery (BCS) followed by radiotherapy (RT) with or without endocrine therapy (ET) is a standard treatment option for ductal carcinoma in situ (DCIS). We sought to investigate national patterns in the use of adjuvant therapy after BCS for hormone receptor (HR)-positive DCIS over time. Using data from the National Cancer Data Base, we identified patients diagnosed with DCIS and treated with BCS between 2004 and 2013. Multivariable logistic regression was used to estimate the odds of adjuvant therapy use controlling for clinicopathologic demographic and facility-level characteristics. We identified 66,079 patients who underwent BCS for DCIS. Overall, 21% received no adjuvant treatment, 71% received RT, 48% received ET, and 38% received the combination therapy. In adjusted analyses among the patients with HR-positive DCIS (n = 50,147), the administration of RT decreased (odds ratio [OR] 0.86, 95% CI 0.77–0.97), while the use of ET increased (OR 1.5, 95% CI 1.4–1.6) in 2013 compared to 2004. Young patients, elderly patients, positive margin status, and Medicare insurance were associated with lower use of both RT and ET. We observed both clinicopathologic and geographic variation in the use of adjuvant therapies. In the lowest risk subgroup, the use of RT decreased from 57% in 2004 to 48% in 2013 (OR 0.64, 95% CI 0.45–0.89). Our study suggests a shift in patterns of care for DCIS that is impacted by both clinicopathologic and demographic factors, with the use of RT decreasing and the use of ET increasing in HR-positive DCIS patients. Current trials are designed to address the possible over-treatment of low-risk DCIS.

Background Although improvements in survival have been achieved for patients with metastatic breast cancer, some patients experience early death after diagnosis. Patients and methods Using Surveillance, Epidemiology, and End Results data, we identified 26,538 patients with de novo metastatic breast cancer diagnosed between January 1, 2000 and June 30, 2011. We evaluated time trends for deaths at 1 and 6 months after diagnosis. We then restricted the cohort to patients diagnosed between 2010 and 2011 (n = 3,317), when human epidermal growth factor receptor 2 was routinely collected, and examined factors associated with early death. Results In 2000, 15.9% of patients died within 1 month of diagnosis and 33.2% within 6 months. In 2011, the proportion of women dying within 1 month decreased to 13.4% and 26.3% within 6 months (p 8.5 higher odds of dying, and uninsured [versus insured] patients had >2.5 higher odds of death). In addition, in some subgroups (e.g., no insurance and triple negative disease), more than half of patients died within 6 months. Region was also associated with early death. Conclusion Although we observed improvements in the proportion of patients experiencing early death, one quarter of patients with de novo metastatic disease diagnosed in 2011 died within 6 months of diagnosis. In addition to tumor factors and older age, geography and uninsured status were associated with early death. Our findings highlight the need for focused interventions for metastatic patients at highest risk for poor outcomes. The Oncologist 2017;22:386-393 IMPLICATIONS FOR PRACTICE: With nearly one quarter of patients in our dataset diagnosed in 2011 dying within 6 months of diagnosis, our findings highlight the persistent and critical need of further characterization and identification of patients who are risk for poor outcomes in order to optimize care, impact change, and improve outcomes for all women with metastatic breast cancer. Our data also emphasize the need for interventions among those at highest risk for early death. These interventions would likely promote immediate referral for clinical trial participation, early palliative care referrals, and additional supportive services, optimizing equitable patient access to cancer treatment and care.

To update and examine national temporal trends in contralateral prophylactic mastectomy (CPM) and determine whether survival differed for invasive breast cancer patients based on hormone receptor (HR) status and age.We identified women diagnosed with unilateral stage I to III breast cancer between 1998 and 2012 within the Surveillance, Epidemiology, and End Results registry. We compared characteristics and temporal trends between patients undergoing breast-conserving surgery, unilateral mastectomy, and CPM. We then performed Cox proportional-hazards regression to examine breast cancer-specific survival (BCSS) and overall survival (OS) in women diagnosed between 1998 and 2007, who underwent breast-conserving surgery with radiation (breast-conserving therapy), unilateral mastectomy, or CPM, with subsequent subgroup analysis stratifying by age and HR status.Of 496,488 women diagnosed with unilateral invasive breast cancer, 59.6% underwent breast-conserving surgery, 33.4% underwent unilateral mastectomy, and 7.0% underwent CPM. Overall, the proportion of women undergoing CPM increased from 3.9% in 2002 to 12.7% in 2012 (P0.001). Reconstructive surgery was performed in 48.3% of CPM patients compared with only 16.0% of unilateral mastectomy patients, with rates of reconstruction with CPM rising from 35.3% in 2002 to 55.4% in 2012 (P0.001). When compared with breast-conserving therapy, we found no significant improvement in BCSS or OS for women undergoing CPM (BCSS: HR 1.08, 95% confidence interval 1.01-1.16; OS: HR 1.08, 95% confidence interval 1.03-1.14), regardless of HR status or age.The use of CPM more than tripled during the study period despite evidence suggesting no survival benefit over breast conservation. Further examination on how to optimally counsel women about surgical options is warranted.

Survivorship care plans (SCP) are recommended for all cancer patients and could be especially useful to survivors 65 years and over ("older"). This study examined receipt of SCPs among older breast cancer survivors and whether SCPs were associated with improved patient-reported outcomes.Three hundred and twenty-eight older women diagnosed with invasive, nonmetastatic breast cancer between 2007-2011 were recruited from 78 cooperative-group sites. Participants completed telephone interviews at baseline and 1-year posttreatment. Regression analyses examined SCP receipt (yes/no) and functioning (EORTC-QLQ-C30), cancer worry, and experiences of survivorship care (care coordination, knowledge).Only 35% of women received SCPs. For each 1-year increase in age, there was a 5% lower odds of receiving an SCP (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.91-0.98, p = 0.007). Besides age, no other factor predicted SCPs. SCP receipt was associated with greater knowledge and understanding of requisite follow-up care (p 0.05); however, functioning was not significantly different among those with vs. without SCPs.Receipt of care plans was limited. SCPs improved understanding of breast cancer follow-up care among older survivors, but did not impact functioning one year post-treatment.To impact functioning and salient needs of the growing cohort of older survivors, survivorship care plans likely should be tailored to geriatric-specific issues. To improve functioning, SCP content should expand to include exercise, nutrition, polypharmacy, social support and management of symptom burden from cancer, and other comorbid conditions. To improve follow-up care for cancer survivors, SCPs should delineate shared care roles between oncology and primary care in managing recurrence surveillance, screening, and cancer sequelae.

BACKGROUND: Despite recent advances in the treatment of patients with metastatic hormone receptor positive (HR+)/HER2- breast cancer (BC), it remains an incurable disease. The activity of immune checkpoint inhibitors (ICI) as monotherapy in patients with metastatic HR+/HER2- BC has been limited. Therefore, the addition of other strategies that elicit an immunogenic tumor microenvironment may be needed. We hypothesize that radiation therapy (RT) will potentiate the efficacy of the PD-1 inhibitor pembrolizumab in patients with metastatic HR+/HER2- BC. METHODS: Trial Design: This is a phase II single arm study assessing objective response rate (ORR) according to RECIST 1.1 in patients with metastatic HR+/HER2- BC who will receive pembrolizumab in combination with palliative RT. Pembrolizumab 200 mg intravenously will be administered 2-7 days before day 1 of RT, and will be given every 21 days until disease progression. Biopsies will be performed in the same lesion at baseline (mandatory if tumor tissue is accessible outside the field of RT) and during cycle 2 within 7-14 days before the day 1 of cycle 3 of pembrolizumab. Key Eligibility Criteria: Patients with metastatic HR+/HER2- BC, with measurable disease outside the field of radiation, for whom palliative RT to at least one bone, lymph node, or soft tissue lesion is indicated. Radiation of visceral lesions (such as lung or hepatic lesions) is not permitted. Although prior RT is allowed, patients must be at least 3 months free from RT; Re-irradiation of the same field is not allowed. There is no limit to the number of previous treatments, and systemic treatment naive patients for metastatic disease are also eligible. Specific Aims: The primary aim is to evaluate the efficacy of the combination, as defined by objective response rate (ORR) outside the field of RT according to RECIST 1.1. Secondary objectives include to determine the ORR according to immune-related criteria, the progression-free survival, the abscopal response rate, the clinical benefit rate, the safety and the tolerability of the combination. In addition, correlative studies will be performed to explore the correlation of immunosuppressive and/or immune-stimulating immune marker profiles at baseline and after cycle 2 to disease response to therapy. Statistical Methods: Using the Simons “optimal” method, in the first stage, 8 patients will be enrolled. If there is at least 1 response, accrual will continue to the second stage where up to 19 additional patients will be enrolled. If at least 3 of these 27 patients have an objective response (≥10%), the regimen will be considered worthy of further study. With this design, the probability of stopping the trial early is 78% if the true response rate is 3%. If the true response rate is 20% the chance that the regimen is declared worthy of further study is 80%. Patient accrual and target accrual: The trial opened in April/2017, and so far, has accrued 2 patients with a target accrual of 27 patients. Accrual should be complete in 14-25 months. Clinical trial information: NCT03051672. Citation Format: Barroso-Sousa R, Gao H, Barry WT, Krop IE, Schoenfeld JD, Tolaney SM. A phase II study of pembrolizumab in combination with palliative radiotherapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-02.

Background: Four large randomized phase III trials have reported significant improvements in disease-free (DFS) and overall survival for H administered with adjuvant polychemotherapy for HER2-positive high-risk BC. With the success of HER2-targeting, limiting chemotherapy is both reasonable and feasible, particularly for smaller, node-negative tumors. However data are limited. Methods: APT is a single arm three-stage, multicenter, phase II study of TH. Patients (pts) with HER2-positive BC (IHC 3 + and/or FISH amplified at > 2.0) with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size < 3 cm were eligible. Pts received T (80 mg/m2) with H (4 mg/kg load ®2 mg/kg) x 12 weekly (w), followed by H x 39 w (2 mg/kg weekly or 6 mg/kg q 3 w). The primary endpoint was DFS. DFS events included invasive local, regional or distant recurrence, contralateral invasive breast cancer and death from any cause. The study had 95% power to distinguish between 3-year failure rates of 9.2% vs. 5% using a Poisson model based on the total patient-years of follow-up (PYFU). Planned interim analyses were designed to stop early for futility at 225 and 800 PYFU, and the regimen would be deemed worthy of further study with Results: 410 pts were enrolled from September 2007 to September 2010 and 406 began protocol therapy. The median age was 55 (range 24-85 years). Sixty-three percent had ER+ tumors. Three percent of tumors were T1mi; T1a; 20% T1b; 41% T1c, and 9% T2 ≤ 3cm. Six pts had a nodal micrometastasis. 356 pts (88%) completed all 52 wks of therapy, with 24 and 6 pts discontinuing due to protocol-specified or other toxicities, respectively. 358 (89%) completed all 12 weeks of combined TH therapy. The most common grade 3/4 toxicities included: neuropathy (4%), neutropenia (4%), transaminitis (3%), leukopenia (2%), fatigue (2%), and hypersensitivity reactions (2%). Reversible symptomatic CHF (grade 3 left ventricular systolic dysfunction) occurred in 2 patients (0.5%). Because of the limited number of events, the Data Safety Monitoring Board approved release of study results with 1316 PYFU and a median follow-up of 3.2 years. A total of 8 DFS events have been observed: 2 pts with metastatic disease, 2 with ipsilateral axillary recurrences, 3 with new contralateral BC (all HER2-), and 1 patient who died after diagnosis of primary ovarian cancer. Conclusion: This represents the first report of TH as adjuvant therapy for node-negative HER2-positive BC. The regimen appears well tolerated and few recurrences have been observed in the study population to date. An updated analysis of efficacy, including estimates of 3-year DFS, will be presented in December when a total of 1520 PYFU in this cohort is anticipated. Based on these early data, the TH regimen may be an acceptable treatment approach for low risk HER2-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-04.