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Purpose: There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records.Methods: We studied the association between BC and RCC in the 2000-2016 Surveillance, Epidemiology and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes.Results: Of the 813,477 females diagnosed with BC in the SEER database, 1,914 later developed RCC. The risk of developing RCC was significantly increased within the first six months, 7-12 months, and 1-5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI, 4.62- 5.57), 2.09 (95% CI, 1.8-2.42), and 1.15 (95% CI, 1.06-1.24), respectively. Of 56,200 females with RCC, 1,087 later developed BC. The risk of developing BC following RCC was elevated within the first six months (SIR of 1.45 [95% CI, 1.20-1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (61.5%) patients. There were 15 germline mutations in those with genetic testing. Conclusion:Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly BC.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background. Given the significant clinical activity of the anti-PD1 inhibitor pembrolizumab as either a single agent or in combination with cytotoxic chemotherapy in the treatment of patients with metastatic triple-negative breast cancer (mTNBC), as well as the favorable cytotoxic and immunomodulatory properties of carboplatin and nab-paclitaxel, we identified a strong rationale to treat patients with mTNBC with the combination of carboplatin (C), nab-paclitaxel (N) and pembrolizumab (P) (CNP). Material and Methods. We undertook a prospective, single-arm pilot study of 30 patients with mTNBC treated at two institutions. Inclusion criteria included: radiographically measurable mTNBC, ECOG performance status of 0-1, Conclusions. CNP demonstrated significant activity in patients with mTNBC. Studies are underway to identify pathologic and genomic correlates of clinical response to CNP. Citation Format: Joseph Baar, Jame Abraham, G. Thomas Budd, Paula Silverman, Alberto Montero, Halle Moore, Pingfu Fu, Vinay Varadan, Kara Ladaika, Lauren Hricik. Pilot study of carboplatin, nab-paclitaxel and pembrolizumab for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-16.

Background: Everolimus in combination with exemestane (EVE+EXE) was initially FDA approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) in patients previously treated with nonsteroidal aromatase inhibitors based on the BOLERO-2 trial. However, none of the patients in the BOLERO-2 trial received prior CDK4/6 inhibitors, which have become standard of care for mHRBC. There is limited data to support the use and clinical benefit of EVE+EXE in mHRBC patients previously treated with CDK4/6 inhibitors. Methods: We reviewed patients ≥18 years old with mHRBC treated with EVE+EXE at our institution from January 1, 2012, to April 1, 2020. Patients were excluded if they received EVE+EXE ≤30 days. Data collected included patient and tumor characteristics, prior therapies in the metastatic setting, adverse drug events, and clinical outcomes. The primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival (OS) and safety. Group comparisons were performed by two-sample t test or Wilcoxon rank sum test for continuous variables and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Log-rank test was used to compare the PFS and OS between groups. Results: One-hundred ninety two patients were included in the study; 79 patients had received prior CDK4/6 inhibitor based therapies, while 113 patients did not. Baseline patient characteristics such as histology, menopause status, de novo metastatic disease, presence of lung or liver metastases, and bone only disease were similar between groups. There was a median of 2 lines of treatment in the metastatic setting prior to receiving EVE+EXE in both groups. Fewer patients received prior chemotherapy in the metastatic setting in those who received prior CDK4/6 inhibitors (32.9% vs 49.6%, p=0.032). In patients who received a prior CDK4/6 inhibitor, median PFS was 3.9 months (95% CI: 3.5 to 4.8) compared to 5.5 months (95% CI: 4.0 to 6.3) in those who did not receive a prior CDK4/6 inhibitor (HR for progression, 1.46; 95% CI: 1.08 to 1.97, p=0.013). Overall survival between groups was not significantly different. A total of 32 (16.7%) patients discontinued EVE+EXE due to intolerance or adverse drug events. Conclusion: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not. Citation Format: Hanjie Mo, Catherine E Renna, Halle CF Moore, Jame Abraham, Megan L Kruse, Alberto J Montero, Susan B LeGrand, G Thomas Budd. Efficacy of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-18.

e19407 Background: The purpose of this study was to evaluate the impact of a continuous improvement process aimed at reducing time to treatment on minimizing the number of days spent to complete pre-treatment visits and the associated costs for patients with non-metastatic breast cancer. Methods: System-wide initiatives were implemented in 2015 to minimize time to treatment initiation (TTI), by incorporating lean process strategies and enhanced coordination. Patient and treatment information was obtained through an IRB-approved registry for the years 2015 and 2018. Average number of days spent to complete visits, TTI, and associated patient costs including driving expenses, parking, food, childcare, and lost wages were calculated and compared between the years 2015 and 2018. Results: In 2015, the median TTI was 43.5 days and the average number of separate days spent to attend multidisciplinary visits prior to first treatment was 1.86. These were reduced to 29 days and 1.52 visits, respectively, in 2018 (p < 0.0001 for both). When evaluating treatment visits by surgical procedure, the average number of visits was reduced regardless of surgical procedure. The average number of visits was highest for patients undergoing mastectomy with reconstruction (2.34 in 2015, reduced to 1.65 in 2018, p < 0.0001). A single visit to complete treatment planning was associated with patient costs of $249 as compared with multiple trips costing $491 for 2 visits and up to $1,226 for 5 visits. Conclusions: In breast cancer patients, implementing a continuous improvement process to reduce time to treatment was associated with fewer visits required prior to treatment initiation, resulting in lower patient costs.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2-positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2-targeting antibodies (trastuzumab and pertuzumab) and antibody-drug conjugates (trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan), clinical outcomes for HER2-positive breast cancer have dramatically changed, and a greater proportion of patients in the nonmetastatic setting are cured. However, in the metastatic setting, resistance to anti-HER2 treatments still remains a major therapeutic challenge, underscoring the importance of developing novel HER2-directed therapies. Over the last year, there has been a dramatic shift in the current treatment paradigms for HER2-positive metastatic breast cancer, with recent U.S. Food and Drug Administration approvals of trastuzumab deruxtecan (DS-8201), neratinib, and tucatinib in combination with trastuzumab and capecitabine. The authors summarize recent phase 3 data with novel HER2-targeted therapies as well as phase 1 and 2 data with other novel HER2-targeting agents.

Background: Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, has shown antitumor activity and a manageable safety profile in several tumor types. Talazoparib, an orally available PARP inhibitor, is approved for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2− locally advanced (LA) or metastatic (M) breast cancer (BC). Preclinical data suggest that PARP inhibitors may have synergistic activity when administered in combination with immune checkpoint inhibitors. We report results from patients with LA/MBC enrolled in the phase 1b/2, multicohort JAVELIN PARP Medley study (NCT03330405). Methods: In phase 1b (cohort 1), patients with advanced solid tumors who had received ≥1 prior standard of care chemotherapy (CT) regimen were treated with avelumab 800 mg IV every 2 weeks (Q2W) in combination with talazoparib 1.0 mg orally once daily (QD) (dose de-escalation to 0.75 or 0.5 mg permitted following toxicity). In 2 phase 2 cohorts, eligible patients had either LA/M triple-negative BC (TNBC, cohort 2A) or LA/M hormone receptor positive (HR+), HER2−, DNA damage repair defect-positive BC (cohort 2B). Patients in cohort 2A had received 0 to 2 prior CT regimens (no progression on prior platinum-based CT) and patients in cohort 2B had received prior standard of care hormone therapy in either the adjuvant and/or LA/M setting followed by 0 to 2 prior CT regimens (no progression on prior platinum-based CT). The primary endpoint for phase 1b was first-cycle dose-limiting toxicities (DLTs) and for phase 2 was objective response (investigator assessed per RECIST v1.1). Adverse events (AEs) were characterized using National Cancer Institute Common Terminology Criteria for AEs v4.03. Results: By the data cutoff on December 24, 2018, 34 patients had been treated in cohorts 1 and 2. Twelve patients with advanced solid tumors were treated in cohort 1 (including 2 patients with TNBC); 3 patients (25.0%) had a first-cycle DLT: grade 3 neutropenia, (n=1) and grade 3 thrombocytopenia, (n=2). Best overall response (BOR) was partial response (PR) in 1 patient, stable disease (SD) in 3, progressive disease (PD) in 6, and non-complete response/non-PD in 1 patient with metastatic castration-resistant prostate cancer and non-measurable disease at baseline; 1 patient was not evaluable for response. Both patients with TNBC had a BOR of SD and remained on treatment for ≥9 months. Objective response rate in this pre-treated and heterogenous population was 8.3% (95% CI, 0.2, 38.5). Based on the phase 1b data, the recommended phase 2 dose was avelumab 800 mg Q2W and talazoparib 1 mg QD. By data cutoff, 22 patients had been treated in cohorts 2A (n=19) and 2B (n=3); median age was 56 and 50 years, respectively. In cohort 2A, 12 patients were evaluable for disease assessment; BOR was PR in 1, SD in 6, and PD in 5. All 3 patients in cohort 2B were non-evaluable for response at data cutoff. Treatment-related AEs (TRAEs) of any grade occurred in 11 patients (91.7%) in cohort 1, and 18 (94.7%) patients in cohort 2A. In cohort 2A, the most common TRAEs were anemia (57.9%), nausea (26.3%), fatigue (21.1%) and thrombocytopenia (21.1%); 9 patients (47.4%) had grade ≥3 TRAEs. There were no treatment-related deaths. Safety data from cohort 2B are not reported owing to low patient numbers. Observed pharmacokinetic (PK) data for avelumab 800 mg Q2W were similar to simulated data derived from a population PK model developed using 10 mg/kg dosing. Conclusions: Avelumab 800 mg Q2W administered in combination with talazoparib 1 mg QD in patients with advanced solid tumors, showed preliminary antitumor activity and a manageable safety profile, which was comparable to the safety profiles of the single agents. The study is ongoing; updated safety and efficacy data, and biomarker data will be presented. Citation Format: Timothy A Yap, Panagiotis Konstantinopoulos, Melinda L. Telli, Smita Saraykar, J Thaddeus Beck, Matthew D. Galsky, Jame Abraham, David R. Wise, Mustafa Khasraw, Gabor Rubovszky, Mikhail Dvorkin, Anil A Joy, Mateusz Opyrchal, Daria Stypinski, Colombe Chappey, Ross Stewart, Rossano Cesari, Anita Scheuber, Aditya Bardia. JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts [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 P1-19-03.

Background: Invasive lobular breast cancer (ILC) is the second most common histological type of invasive breast cancer and accounts for 10-15% of all breast cancer cases. It is commonly strongly hormone receptor positive and, in general, is considered to be less chemo-sensitive compared with invasive ductal carcinoma (IDC). The aim of this study was to compare survival outcomes among ILC patients treated with adjuvant endocrine therapy (ET) compared with chemoendocrine therapy (CET). We also sought to assess utilization of Oncotype Dx testing and distribution of Recurrence Score results among ILC patients treated at our institution. Methods: We conducted an IRB approved retrospective study at Cleveland Clinic Taussig Cancer Institute of patients with non-metastatic ILC. Patient diagnosed with ILC and treated from January 2004 through December 2017 were identified from our tumor registry. Patient characteristics including demographics, pathologic features, hormone replacement therapy (HRT) use, Oncotype Dx recurrence score, treatment details and recurrence data were obtained through medical chart review. Recurrence-free and overall survival (OS) were compared between ET and CET using Kaplan-Meier method and Cox proportional hazard model with consideration of differences on age and prognostic factors. The outcomes between age and pathological stage propensity score matched treatment groups were also compared. Results: A total of 638 patients (Mean age 61.9±11.7, 99.1% estrogen receptor positive, 82.6% progesterone receptor positive) were identified. 406 (63.6%) patients received ET and 232 (36.4%) patients received CET. Compared to ET, patients who received CET were significantly younger (Mean 56.3 vs 65.0 years) and more likely to be premenopausal (40.1% vs 14.6%), however they had significant worse prognostic features including pathological stage (stage III: 38.9% vs 2.1%), grade (≥ II: 69.0% vs 55.9%) and Oncotype Dx score (≥18: 72.4% vs 36.2%). Patients were followed for median (IQR) time of 4 (2.0, 6.4) years for survival outcomes. Although recurrence-free survival (local or distant) was worse in CET (5-year recurrence-free: 81.9% vs 96.5%), age and clinical prognostic features adjusted recurrence risk was similar as ET (Adjusted HR and 95% CI: 0.83, 0.36-1.92) and risk of death was also similar (Adjusted HR and 95% CI: 0.68, 0.31-1.50). Only 222 patients had Oncotype Dx score (35%), with 59% falling in the low risk range, 39% intermediate risk range and 2% high risk range. The Oncotype Dx recurrence score was not associated with recurrence or death. The recurrence-free (5-year: 97.4% vs 90.4%, p=0.37) and OS (At 5-year OS: 94.3% vs 89.4%, p=0.08) were also similar between age and pathological stage matched CET and ET groups. Conclusion: Use of chemoendocrine therapy did not result in improved survival outcomes for patients with ILC compared to those treated with endocrine monotherapy in the adjuvant setting. The majority of ILC patients did not have Oncotype Dx testing sent however when it was ordered, most cases resulted in the low-intermediate risk range, suggesting limited benefit of chemotherapy as reflected by survival outcome results observed. Citation Format: Mathew Thomas, Hong Li, Jame Abraham, Halle CF Moore, G Thomas Budd, Alberto J Montero, Megan L Kruse. Comparison of survival outcomes between treatment with endocrine therapy and chemoendocrine therapy in patients with invasive lobular carcinoma [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 P2-14-13.

Background: Although the advent of targeted therapy has substantially improved outcomes for HER2+ breast cancer patients, many will still fail to achieve pathological complete response (pCR) following neoadjuvant chemotherapy (NAC). In order to reduce overtreatment among patients resistant to standard HER2-targeted NAC and identify candidates for alternative therapeutic interventions, there is a need for validated markers of anti-HER2 agent benefit. The computational analysis of pretreatment imaging has shown recent promise in identifying responsive breast cancers. However, previous applications have explored response prediction among cohorts of mixed subtype and therapeutic approach, thus limiting its relevance in informing specific therapeutic strategy. Methods: This study comprised retrospective contrast-enhanced MRI data from a total of 159 patients who received anti-HER2 therapy at 5 institutions. A deep learning (DL) model was trained and tuned using 100 HER2+ breast cancer patients who received neoadjuvant taxane (T), carboplatin (C), trastuzumab (H), and pertuzumab (P) at Institution A, of which 49 achieved pCR (ypT0/is). A convolutional neural network was designed to analyze pre- and post-contrast MRI images acquired before NAC and compute a patient's probability of achieving pCR. Institution A data was split randomly into a 85 patient training cohort, used to directly train the model, and a 15 patient internal validation cohort, used to monitor and improve training progress. Two external, held-out testing datasets were used to evaluate capability to predict response in HER2+: Testing Cohort 1, consisting of 28 patients (16 pCR, 12 non-pCR) treated with TCHP at Institution B, and Testing Cohort 2, consisting of 29 patients (10 pCR, 19 non-pCR) who received TCH at one of 3 other institutions as part of the BrUOG 211B trial. A multivariable clinical model (MCM) incorporating age, ER/PR status, stage, and size was evaluated separately and in combination with the neural network. Performance was assessed by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. Results: The neural network was able to strongly predict response to HER2-targeted NAC in the internal validation (AUC=.93) and testing cohorts (AUC=.84 and AUC=.77). This model offered superior performance compared to a MCM, which performed poorly across institutions. Strikingly, the higher accuracy of DL included correctly identifying responders within the ER+/PR+ subgroup of patients and non-responders within the ER-/PR- subgroup. Combining DL predictions with the clinical model improved performance to AUC of 0.89 in testing cohort 1, but did not improve AUC in cohort 2. Conclusions: DL analysis of breast DCE-MRI could be used to better identify benefit of HER2-targeted therapeutic approaches prior to administration. As the first exploration of automated response prediction from imaging with respect to a targeted NAC approach, this work uniquely has the potential to help guide therapeutic decision-making. Our approach was effective in predicting response to multiple HER2-targeted NAC regimens, with better performance in the cohort who received TCHP (as in the training cohort). The strong performance of this model across 5 institutions is a promising indicator of its robustness and ability to tailor therapy even within clinically-distinct HER2+ patient subpopulations. Deep learning (DL) and multivariable clinical model (MCM) pCR prediction by cohortCohortModelAUC (%)Sensitivity (%)Specificity (%)Accuracy (%)Validation (n=15, 53% pCR)DL93888687MCM66637173Testing 1 (n=28, 57% pCR)DL85889289MCM54388350DL+MCM89819286Testing 2 (n=29, 34% pCR)DL77708479MCM53208966DL+MCM76808483 Citation Format: Nathaniel Braman, Mohammed El Adoui, Manasa Vulchi, Paulette Turk, Maryam Etesami, Pingfu Fu, Stylianos Drisis, Vinay Varadan, Donna Plecha, Mohammed Benjelloun, Jame Abraham, Anant Madabhushi. Validation of neural network approach for the prediction of HER2-targeted neoadjuvant chemotherapy response from pretreatment MRI: A multi-site study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-13.

Background: Angiogenesis is crucial to a tumor's growth and an important factor in therapeutic outcome. Although quantitative analysis of tumors on dynamic contrast enhanced (DCE) MRI can provide indirect characterization of a tumor's vascularization, direct computational analysis of the tumor-associated vessel network remains a promising, but under-explored potential marker of therapeutic response. For instance, surrounding vasculature with a convoluted 3-dimensional shape and poor blood flow may indicate a more aggressive tumor and poorly facilitate delivery of therapeutic agents. In this work, we present a computational approach for the prediction of neoadjuvant chemotherapy response using quantitative imaging features describing the morphology and function of tumor associated vasculature on pretreatment MRI. Methods: 243 patients who received DCE-MRI scans prior to neo-adjuvant chemotherapy (NAC) at institution A [n=83], B [n=76], or one of nine other institutions as part of the ISPY1 Trial [n=84] were divided randomly into training (n=123) and testing (n=120) sets. 148 patients were HER2- and received neoadjuvant AC-T, while the 95 HER2+ patients were treated with TCHP (ISPY predates anti-HER2 therapy and HER2+ ISPY patients were excluded). 79 patients achieved pathological complete response [pCR, ypT0/is] following NAC. MRI exams were collected with a 1.5 or 3 Tesla scanner in the axial or sagittal plane. A baseline scan and 2-5 scans after injection of a gadolinium-based contrast agent with a median temporal resolution of 2.5 minutes were acquired. A portion of the tumor was manually delineated, then semi-automatically expanded to 3D. Vasculature was isolated from subtraction images with a specialized filtering approach to detect vessel-shaped objects. Features describing the 3D shape and architecture of the tumor-associated vessel network (e.g. curvature, torsion, and local orientation) and functional semi-quantitative pharmacokinetic (PK) measurements of temporal contrast enhancement changes (e.g. signal enhancement ratio, time to peak enhancement, and rates of uptake and washout) were calculated. Performance was assessed by area under the receiver operating characteristic curve (AUC), as well as the accuracy, sensitivity, and specificity at the operating point corresponding to the Youden Index. The most discriminating features were determined based on frequency of selection by the random forest classifier. Results: Within the training set, PK parameters of the vessels (AUC=.66) outperformed relative to the PK of tumor (AUC=.63) and the PK of peritumoral regions (AUC=.64); however, a combination of the three yielded best performance (AUC=.75). Vessel shape features alone achieved AUC=.67 in the training set. When multi-region PK features and tumor shape features were combined and applied to the 120-patient independent testing set, the random forest classifier achieved an AUC of 0.70 and identified 81% of patients who would achieve pCR. Non-pCR was best characterized by increased vessel curvature and PK parameters indicating poor perfusion, such as greater time to peak enhancement, slower uptake rate, and quicker washout. Conclusions: Our findings suggest that properties of the tumor-associated vessel network, such as its shape and enhancement profile, might provide value in identifying patients who will respond to NAC before administration of treatment. Accuracy (%)Sensitivity (%)Specificity (%)Full testing set (n=120)678160HER2+ (n=44)709548HER2- (n=76)646365HER2-, HR+ (n=51)678364Triple Negative (n=25)605067 Citation Format: Nathaniel Braman, Prateek Prasanna, Kaustav Bera, Mehdi Alilou, Manasa Vulchi, Maryam Etesami, Paulette Turk, Jame Abraham, Donna Plecha, Anant Madabhushi. Radiomic measurements of tumor-associated vasculature morphology and function on pretreatment dynamic MRI identifies responders to neoadjuvant chemotherapy [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 P1-10-06.

BACKGROUND Genetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer. METHODS A prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer. RESULTS Prospective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03). CONCLUSION Adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer. FUNDING National Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.

PURPOSE Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab. PATIENTS AND METHODS In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally. RESULTS Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell–free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue. CONCLUSION We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.

Patients were treated at a single institution to a dose of 30 Gy in five fractions delivered every other day using image-guided intensity modulated radiation therapy (IMRT) partial breast irradiation. A total of 34 patients were treated with a median follow-up of 4.6 months. The rate of acute Grade 1 dermatitis was 23.5% (n = 8), and Grade 1 fatigue was 17.6% (n = 6), with no Grade 2 or higher acute toxicities. The rate of chronic Grade 1 dermatitis was 25.0% (n = 6), Grade 1 fat necrosis 4.2% (n=1), with no patients demonstrating other chronic toxicities. Image-guided APBI delivered with IMRT is associated with low rates of acute and chronic toxicity though additional follow-up is warranted.

Patients with breast cancer receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM). GSM can decrease quality of life and is undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy because of unknown levels of systemic absorption of estradiol. In this article, we review the available literature for treatment of GSM in patients with breast cancer and survivors, including nonhormonal, vaginal hormonal, and systemic hormonal therapy options. First-line treatment includes nonhormonal therapy with vaginal moisturizers, lubricants, and gels. Although initial studies showed significant improvement in symptoms, the US Food and Drug Administration recently issued a warning against CO2 laser therapy for treatment of GSM until additional studies are conducted. In severe or refractory GSM, after discussing risks and benefits of vaginal hormonal therapy, the low-dose 10-μg estradiol-releasing intravaginal tablet or lower-dose 4 μg estrogen vaginal insert and intravaginal dehydroepiandrosterone (prasterone) are options for treatment, because studies show minimal elevation in serum estradiol levels and significant improvement in symptoms. The decision to offer vaginal estrogen therapy must be individualized and made jointly with the patient and her oncologist.

Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer after invasive ductal carcinoma (IDC). Invasive lobular carcinoma has unique clinical, pathologic, and radiographic features which suggest that it is a distinct clinical entity; however, it is treated with the same treatment paradigms as IDC. Information regarding the specific treatment of ILC, including response to standard therapy, is sparse. Neoadjuvant treatment considerations are of great importance in this space as ILC is often found at a locally advanced stage. In this review, we summarize the classic features of ILC and the available data regarding efficacy of both endocrine therapy and chemotherapy in curative treatment of breast cancer.

Real-world data are critical to demonstrate the reproducibility of evidence and external generalizability of randomized clinical trials. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to improve progression-free survival (PFS) when combined with letrozole or fulvestrant in phase 3 clinical trials. We evaluated real-world outcomes in metastatic breast cancer patients who received palbociclib in combination with endocrine therapy in routine clinical practice. Records of patients with advanced hormone receptor (HR)-positive breast cancer treated with palbociclib at the Cleveland Clinic health system from February, 2015 to December, 2017 were retrospectively reviewed. The primary end point was PFS. In this cohort, 411 women were included. The median age and follow-up times were 53.5 years and 10.2 months, respectively. The median PFS for palbociclib plus letrozole was 15.1 months for patients treated in first line, 10.5 months in second line, and 4.2 months in third line and beyond. For patients who received fulvestrant plus palbociclib, the median PFS in first, second, and third line and beyond were 11.6, 12.3, and 6.4 months, respectively. The most common adverse events were hematologic, with grade 3–4 neutropenia occurring in 58% of patients. Thirty-one (8%) patients permanently discontinued palbociclib due to adverse events. Among patients with HR-positive advanced breast cancer, the estimated PFS in patients treated with fulvestrant and palbociclib was comparable to a previously reported phase 3 trial. However, the median PFS with letrozole and palbociclib was shorter than previously reported data from phase 2 and 3 trials. Palbociclib toxicity was very manageable, with a low drug discontinuation rate.

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

BackgroundPseudocirrhosis is characterized by radiological changes in the liver that resemble cirrhosis, but with more rapid onset and progression. Though reported most frequently in patients with metastatic breast cancer, little is known about its prognostic factors and impact on breast cancer outcomes.MethodsIn this observational study, we reviewed abdominal CT and/or MRI scan reports of all patients with invasive breast cancer diagnosed at our center, during a ten-year period, to identify patients with pseudocirrhosis. Exclusion criteria included lack of baseline imaging, pre-existing cirrhosis, hepatitis B or C, other chronic liver diseases, or heavy alcohol use. Routine descriptive statistical measures were used. Survival distributions were estimated using Kaplan-Meier method, and Cox regression was used for multivariate analysis. Two-tailed p < 0.05 was considered significant.ResultsEighty-six patients were included – all were females, median age was 57.5 years, and 90% were Caucasian; 86% of primary tumors were hormone-receptor positive and 17% were HER2 positive. Most patients (98%) had metastatic disease with liver involvement (94%), and were heavily pre-treated – 97% with chemotherapy, 85% with hormonal therapy, and 19% with anti-HER2 agents. Median interval from breast cancer diagnosis to pseudocirrhosis was 75.4 months (IQR 35.2-115.3 months). Thirty-six percentage of patients had ≥1 signs of portal hypertension and 49% had ≥1 signs of hepatocellular failure. Pseudocirrhosis led to permanent discontinuation of chemotherapy, endocrine therapy, and all systemic therapies in 29%, 31%, and 20% patients, respectively. Median overall survival from diagnosis of pseudocirrhosis was 10.0 months (95%CI 5.2-14.8 months). On multivariate analysis, coagulopathy, hyperbilirubinemia, hypoalbuminemia, and cancer progression were independently predictive of mortality.ConclusionsIn this largest series, to date, of breast cancer with pseudocirrhosis, the latter was often complicated by portal hypertension and hepatocellular failure, and markedly impacted breast cancer management. Survival was shorter for patients who developed hepatocellular failure.

Through expert, case-based discussion, Jame Abraham, MD, and Kelley Mayden, MSN, FNP, AOCNP®, presented existing and emerging data for current and investigational therapies for HER2-positive breast cancer and their associated adverse events, in addition to best practices for managing central nervous system metastases.

This article reviews the available literature that describes the incidence, diagnosis, mechanism, symptoms, and management of pulmonary toxicity induced by radiation therapy and current systemic medications used to treat breast cancer. An extensive literature search was conducted via Ovid Medline to identify all potentially relevant articles written in English from 2010 through January 2020. Additional relevant articles outside the time frame were included as needed. Although the risk of pulmonary toxicity from various breast cancer treatments is small in most instances, it can be fatal. Due to the high prevalence of breast cancer and the range of treatment options, healthcare providers should be aware of the risk of pulmonary toxicity from those treatments and how to prevent or manage complications.

Introduction: Cyclin-dependent kinase (CDK) 4/6 inhibitors have altered the standard-of-care treatment for patients with ER-positive, HER2-negative metastatic breast cancer. One such inhibitor, abe...

To evaluate the temporal relations of cardiovascular disease in oncology patients referred to cardio-oncology and describe the impact of cardiovascular disease and cardiovascular risk factors on outcomes. All adult oncology patients referred to the cardio-oncology service at the Cleveland Clinic from January 2011 to June 2018 were included in the study. Comprehensive clinical information were collected. The impact on survival of temporal trends of cardiovascular disease in oncology patients were assessed with a Cox proportional hazards model and time-varying covariate adjustment for confounders. In total, 6,754 patients were included in the study (median age, 57 years; [interquartile range, 47 to 65 years]; 3,898 women [58%]; oncology history [60% - breast cancer, lymphoma, and leukemia]). Mortality and diagnosis of clinical cardiac disease peaked around the time of chemotherapy. 2,293 patients (34%) were diagnosed with a new cardiovascular risk factor after chemotherapy, over half of which were identified in the first year after cancer diagnosis. Patients with preexisting and post-chemotherapy cardiovascular disease had significantly worse outcomes than patients that did not develop any cardiovascular disease (p < 0.0001). The highest 1-year hazard ratios (HR) of post-chemotherapy cardiovascular disease were significantly associated with male (HR 1.81; 95% confidence interval 1.55 to 2.11; p < 0.001] and diabetes [HR 1.51; 95% confidence interval 1.26 to 1.81; p < 0.001]. In conclusion, patients referred to cardio-oncology, first diagnosis of cardiac events peaked around the time of chemotherapy. Those with preexisting or post-chemotherapy cardiovascular disease had worse survival. In addition to a high rate of cardiovascular risk factors at baseline, risk factor profile worsened over course of follow-up.

Background CDK4/6 inhibitors (CDK4/6i), in combination with aromatase inhibitors, are United States Food and Drug Administration-approved for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). The effectiveness of continuing them beyond first disease progression (PD) is currently unknown. This retrospective study evaluated the impact of the continuation of CDK4/6i beyond first PD in HR+/HER2− MBC using real-world experience. Patients and Methods A single-institution retrospective review of patients with HR+ MBC who received CDK4/6is from 2015 to 2018 and where CDK4/6is were continued beyond first PD. The primary outcome was progression-free survival (PFS) after initial PD on CDK4/6i therapy. Results Thirty women with HR+/HER2− MBC met eligibility criteria. Patients were identified from a prospective database of patients at the Cleveland Clinic Foundation who were prescribed CDK4/6is. The median age and follow-up duration were 47.5 years and 27 months, respectively. Most patients received palbociclib (PA)/letrozole as initial therapy (67%), followed by PA/fulvestrant (23%), and PA/other aromatase inhibitor (20%), and abemaciclib with either fulvestrant or letrozole (6%). As of January 31, 2019, 25 (83.3%) patients were still alive, and 19 (63%) patients had progressed. The estimated median PFS for continued CDK4/6i use beyond the first PD was 11.8 months (95% confidence interval, 5.34-13.13 months). Conclusions Among a small cohort of patients with HR+ MBC in a non-clinical trial setting, continuation of CDK4/6i-endocrine treatment post initial PD was associated with a median PFS of about 12 months. Formal randomized clinical trials evaluating the continuation of CDK4/6is beyond the first PD are currently ongoing and will provide more answers to this important clinical question.

Poor lifestyle choices play a significant role in the development and progression of preventable chronic diseases, including cancer. In this study, we evaluate the effectiveness of a comprehensive lifestyle medicine intervention on chronic disease risk factors and quality of life in breast cancer survivors.This is a retrospective review of a clinical program from January 2016 to July 2017.It includes seven 2-h group medical visits held every other week at an outpatient wellness facility.Eligible participants are breast cancer survivors who have completed treatment, including those who remain on hormonal therapy.Patients receive education and experience in nutrition, culinary medicine, physical activity, and stress relief practices.Participants' weight, body mass index (BMI), body fat mass, lean body mass, and percent body fat were measured at visit 1 and visit 7. Standard validated questionnaires were used to measure perceived stress, depression, patient activation, physical and mental quality of life, dietary fat consumption, and dietary fruit, vegetable, and fiber consumption.A total of 31 patients participated in the group visits. Pre-post comparison data were not available for 10 patients. More than three-quarters of the 21 breast cancer survivors who attended 5 or more of the 7 group visits and provided data at the first and the last group visit decreased their body weight. On average, patients lost 4.9 pounds (-2.6%, p 0.01), and their BMI decreased by 0.8 kg/mBreast cancer survivors could employ the prescribed lifestyle modifications to produce clinically relevant health benefits. Interdisciplinary teams of health care professionals may help breast cancer survivors with chronic diseases implement evidence-based, individualized, and effective lifestyle prescription through group medical visits.

Breast cancer treatment often requires multi-disciplinary evaluation, which can require multiple visits, delaying time to treatment initiation (TTI). The present analysis evaluated the impact of system-wide initiatives to reduce TTI by evaluating TTI for patients completing treatment evaluation in a single visit compared with those having multiple visits. The results demonstrated that patients who completed multi-disciplinary evaluation in a single visit had a reduced median TTI (27 vs 32 days, P = .002), which was seen for patients undergoing initial surgery (28.0 vs 33.5 days, P = .01) as well as for those undergoing neoadjuvant systemic therapy (22.5 vs 29 days, P = .05).

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

This study investigated patients with invasive lobular breast carcinoma (ILC) to determine the benefit of neoadjuvant systemic therapy (NAST).Patients with ILC treated from 2006 to 2015 were identified. Tumor characteristics and treatment data were analyzed.Of the 560 patients with ILC, 77 patients received NAST. Patients who received NAST presented with larger clinical T stages compared to patients who received surgery first (p 0.001). Pathological complete response (pCR) to NAST was seen in 17% of patients. Only 14% of patients with clinically positive lymph nodes downstaged to N0. These patients were more likely to have HER2 positive tumors (p 0.029) and larger tumor size at diagnosis (p 0.015). Mastectomy was performed in 84% of patients and lumpectomy in 16%.Only a minority of patients with ILC achieve pCR. The majority of patients still undergo mastectomy; therefore the benefit of NAST in ILC appears limited.

Background : The pivotal phase III EMILIA trial reported a progression free survival (PFS) rate of 9.6 months and an objective response rate of 43% with T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. However, there is very limited data on the efficacy of T-DM1 in patients who have received prior pertuzumab either neoadjuvantly or as first line therapy in the metastatic setting. The primary goal of this study was to assess the clinical efficacy (tumor response rates and median duration on therapy) of T-DM1 in patients previously treated with pertuzumab and trastuzumab. Methods: After IRB approval, a cancer data registry and electronic pharmacy database were utilized to identify breast cancer patients receiving treatment with T-DM1 at Cleveland Clinic and University of Pittsburgh. Patients that received trastuzumab and pertuzumab, in either the neoadjuvant or metastatic setting, with baseline and follow up imaging available for review were identified. Patient charts were reviewed to collect accurate information about the treatment sequencing and outcomes. RECIST version 1.1 was utilized for tumor assessment and patients with measurable disease and non measurable disease were included in the study. Results: We identified a total of 23 patients with a median age of 55 years that met the inclusion criteria. 69% percent of patients received T-DM1 as first line or second line therapy and 31% received it as third line or later. All patients had at least 1 measurable lesion. Best overall response showed rates of complete response, partial response and stable disease of 17%, 26% and 22% respectively. 35% patients progressed on first assessment after start of treatment. The median duration on therapy was 5.3 months (range 3 weeks to 33 months) with 43% of patients receiving T-DM1 for greater than 6 months. Conclusion: Our results were comparable to those reported by EMILIA trial. T-DM1 has reasonable clinical efficacy in patients who have received prior treatment with pertuzumab and trastuzumab with an overall response rate of 43% and median duration on therapy of 5.3 months. Citation Format: Tiwari SR, Sussman T, Kota K, Moore HC, Montero AJ, Budd GT, Puhalha S, Abraham J. T-DM1 activity in metastatic HER2-positive breast cancer patients who have received prior trastuzumab and pertuzumab: NSABP B-005 [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 P5-21-26.

Background Hepatic pseudocirrhosis (HP) is a rare entity characterized by radiological changes in the liver resembling cirrhosis (lobular contour, nodularity, capsular retraction, and atrophy), reported most frequently in patients (pts) with treated metastatic breast cancer (BC). Cases in literature have been associated with poorer prognosis than true cirrhosis with fatal outcome nearly always in a few months. Little is known about factors which predispose to HP or influence its prognosis. Methods In this retrospective observational study, we reviewed abdominal radiology reports (CT, MRI, and ultrasound scans) of all our pts with BC diagnosed between 01/01/07 and 12/31/16, to identify those with HP. Cirrhosis on baseline imaging, pre-existing chronic liver disease, hepatitis B/C, and heavy alcohol use were exclusion criteria. Routine descriptive statistical measures were employed. Multiple regression was used to analyze factors affecting survival. p Results We identified 86 pts with HP who satisfied inclusion/exclusion criteria. All were females, 89.5% were Caucasian. 83.7% of primary tumors were ER+, 58.1% were PR+ and 17.4% were HER2+. 25.6% had an invasive lobular component. The vast majority had distant metastases (mets) (97.7%) and liver mets (94.2%) at the time of diagnosis of HP, though 52.3% had stage I/II BC on initial presentation. Median size of the largest liver met was 30.0 mm and 87.2% pts had >10 liver mets. Most pts were heavily pre-treated before the manifestation of HP – 84.9% had received hormonal therapy (median cumulative duration of 35 months each of tamoxifen and aromatase inhibitors), 18.6% got anti-HER2 therapy (median duration of 15 months), and 96.5% received chemotherapy (81.4% had received ≥ 2 lines of chemotherapy). Median interval from diagnosis of BC to detection of HP was 6.3 years (IQR 2.9-9.6). 36% had ≥1 signs of portal hypertension (splenomegaly 15.1%, esophageal/gastric varices 18.6%, variceal bleeding 9.3% and ascites with high albumin gradient 34.9%), while 48.8% had ≥1 signs of hepatocellular failure (jaundice 47.7%, coagulopathy 30.2%, hepatic encephalopathy 14.0%). Detection of HP often led to changes in BC therapy – chemotherapy was changed in 46.5% pts, stopped in 24.4%, hormonal therapy was changed in 18.6%, stopped in 15.1%, and hospice care was initiated in 19.8% pts. Status of BC and liver mets at initial detection of HP were variable – 53.5% had disease progression while 45.3% had continued response; 40.7% had enlarging, 23.4% had stable and 30.9% had shrinking liver mets. Median survival after detection was HP was 3.6 months (1.1-11.5). Death was due to BC-progression in 83.4% pts and HP-related complications (GI bleeding, hepatic failure) contributed in 28.6% pts. Using multiple regression, lower albumin level and a higher number of metastatic sites at initial detection of HP were found to be independently associated with shorter post-HP survival (R2 16.6%, F(2,74) 7.37, p=0.001). Conclusions We report the largest series, till date, of BC patients with HP, an entity which can be complicated by portal hypertension and hepatocellular failure, and with marked impact on BC survival and management. Studies are needed to identify risk factors and management strategies. Citation Format: Gopalakrishnan D, Abraham J. Hepatic pseudocirrhosis in breast cancer – analyses of clinical and prognostic factors [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 P3-14-04.

Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.

Genomic profiling can identify targetable mutations; however, the impact of tissue-based genomic profiling on clinical decision making for patients with metastatic breast cancer has not been well characterized. Patients with stage IV breast cancer who had undergone genomic profiling between 7/2013 and 3/2015 were identified at three academic cancer centers. Genomic analysis was determined to have impacted clinical decision if (A) a patient was enrolled onto a genotype-matched clinical trial or (B) prescribed off-label an FDA-approved therapy targeting an identified mutation. The frequency of mutated genes was determined. A total of 117 patients with stage IV breast cancer were identified. Median age was 46 (25–75). Fifty-three patients (45%) had ER-positive/HER2-negative disease, 50 (43%) had ER-negative/HER2-negative disease, and 14 (12%) had ER-any/HER2-positive disease. Median number of previous therapies received prior to genomic profiling was 2 (range 0–15), and median follow-up after testing was obtained after 5.8 months (range 0–24.4 months). Commercial reports indicated that 85 (73%) patients had at least one mutation targetable by an FDA-approved medication, and 112 (96%) patients had at least one clinical trial available; however, clinical management was only affected in 11 patients (9%). The most frequent mutations observed were those in TP53, FGF, PI3KCA, MYC, ZNF, FGFR, CCND, ARID1A, GATA3, and MAP; frequencies of these mutations varied by clinical subtype. Tumor genomic profiling affected clinical management in a minority of patients with metastatic breast cancer, thus these data do not support the routine use of genomic profiling outside of a clinical trial.

Background: Genetic counseling and fertility resources are often underutilized in young women with early stage breast cancer (ESBC) due, in part, to concerns about treatment delays. At our institution, women newly diagnosed with ESBC typically see a breast surgeon, medical oncologist and radiation oncologist in a multidisciplinary clinic with additional cancer related subspecialist referrals occurring at those providers' discretion. We hypothesized that time to treatment (TTT) and utilization of fertility, genetics and social work consultations would improve after implementing a Young Women's Breast Cancer Clinic. As of January 1, 2015, all patients under age 50 seen at Cleveland Clinic for new diagnosis of ESBC were automatically offered scheduling of appointments with medical genetics, reproductive endocrinology and social work in addition to the usual multidisciplinary team. Methods: Women under age 50 diagnosed with ESBC seen at Cleveland Clinic from 1/2014-12/2015 were identified using our tumor registry. Demographics, tumor pathology, clinical and treatment histories were obtained through medical chart review as per IRB approved protocol. Time from initial visit in our system to date of treatment initiation was calculated for all patients and compared between the 2014 (pre-intervention) and 2015 (post-intervention) cohorts as was time from diagnosis (biopsy date) to treatment initiation. Completed reproductive endocrinology, genetic counseling and social work consultations were documented. Welch two sample t-test was used to compare time to treatment between groups. Chi squared test was used to compare frequency of subspecialty consultations between groups. Results: 207 young women with ESBC were identified over the 2 year period, 99 in 2014 and 108 in 2015. Median age was 45 in 2014 and 44 in 2015. Most were diagnosed outside of our hospital system, 58% in 2014 and 76% in 2015. The most common initial treatment was surgery with reconstruction (S+R) (54% and 50% for 2014 and 2015 respectively) followed by chemotherapy (23% and 27%) then surgery without reconstruction (S) (20% and 24%). Median TTT from first encounter was 30 days in 2014 and 28 days in 2015 (p=0.33) and was 36 days versus 33.5 days (p=0.23) when calculated from biopsy date. TTT in the S and S+R groups was 37 vs 28 days (p=0.84) and 36.5 vs 32 days, (p=0.21), respectively. Genetics, reproductive endocrinology and social work consults in 2014 vs 2015 were documented as 89% vs 94%, 4% vs 9% and 58 vs% 55% (p=0.22, 0.32, 0.77). For patients under age 40, 27% in 2014 and 30% in 2015 completed reproductive endocrinology consultations. Conclusions: Offering upfront scheduling of breast cancer related subspecialty appointments for young women with newly diagnosed ESBC did not significantly improve overall TTT. There was a trend towards improved TTT in those receiving surgery with or without reconstruction as first treatment and no suggestion of delay in TTT. A modest numeric increase in completed genetic counseling and reproductive endocrinology consultations was not statistically significant, but may have been clinically meaningful for affected individuals. Citation Format: Kruse ML, Raska P, Abraham J, Budd GT, Montero A, Grobmyer S, Moore H. Impact of institution of young women's breast cancer clinic on time to treatment and utilization of fertility, genetics and social work consultations in women under age 50 with new diagnosis of early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-12-04.

The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34–66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24–54]) or neratinib (33% [95%CI 20–50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR−) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR− patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

The CDK4/6 inhibitors – palbociclib, abemaciclib, and ribociclib – have been approved to be used with aromatase inhibitors/fulvestrant in the setting of advanced, hormone receptor-positive breast c...

BACKGROUND: Patients with breast cancer positive for human epidermal growth factor receptor 2 (HER2) remain at high risk of intracranial relapse following treatment and experience increased rates of intracranial failure after stereotactic radiosurgery (SRS). We hypothesized that the addition of concurrent lapatinib to SRS would improve intracranial complete response rates. METHODS: Patients with newly diagnosed HER2-amplified breast cancer brain metastases from 2005–2014 who underwent SRS were included and divided into 2 cohorts based on timing of treatment with lapatinib. Outcome variables included the proportion of patients who achieved an intracranial complete response or progressive disease according to the RECIST 1.1 criteria, as well as individual lesion response rates, distant intracranial failure, and radiation necrosis. RESULTS: Eighty-four patients with 487 brain metastases met inclusion criteria during the study period. Over 138 treatment sessions, 132 lesions (27%) were treated with SRS and concurrent lapatinib, while 355 (73%) were treated with SRS without lapatinib. Compared with patients treated with SRS alone, patients treated with concurrent lapatinib had higher rates of complete response (35% vs 11%, P = 0.008). On a per-lesion basis, best objective response was superior in the concurrent lapatinib group (median 100% vs 70% reduction, P < 0.001). Concurrent lapatinib was not associated with an increased risk of grade 2+ radiation necrosis (1.0% with concurrent lapatinib vs 3.5% without, P = 0.27). Lapatinib had no protective effect on distant intracranial failure rates (48% vs 49%, P = 0.91). CONCLUSION: The addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases.

10503 Background: Genetic factors that contribute to endogenous estrogen synthesis and postmenopausal breast cancer risk are unknown. We set out to test the hypothesis that homozygous inheritance of the common 1245A→C missense-encoding polymorphism in HSD3B1, which is common (8-10%) in White populations, functionally adrenal permissive and increases synthesis of the aromatase substrate, androstenedione, is associated with postmenopausal estrogen receptor-positive breast cancer. Methods: A prospective single institution study of postmenopausal estrogen receptor-driven breast cancer for determination of HSD3B1 genotype, circulating steroid concentrations, and adrenal-permissive genotype frequency compared with the genotype frequency in the general population and in estrogen receptor-negative breast cancer. Validation was performed in 2 breast cancer genomic studies with estrogen receptor documentation. The primary outcome is the adrenal-permissive genotype frequency in postmenopausal estrogen receptor-positive breast cancer and the general population. Genotype comparisons were also done with postmenopausal estrogen receptor-negative breast cancer and the association with circulating adrenal androgen concentrations determined. Results: The prospective and validation studies had 199 and 1628 women, respectively. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 9.6% (429/4451) in the general population [p = 0.0077]. The adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using the Cambridge and TCGA genomic datasets together: 14.4% (56/389) compared with 6.0% (9/149) for estrogen receptor-negative breast cancer (p = 0.007) and the general population (p = 0.005). Circulating androstenedione concentration was significantly higher for women with the adrenal-permissive genotype compared with the other genotypes (p = 0.03). Conclusions: The adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer and have broad implications for risk stratification, prevention, potential biomarkers for hormonal therapy response and possibly other clinical outcomes related to estrogen physiology in postmenopausal women.

Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-03.

HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice.

Background: Breast cancer is the most common cancer among African American (AA) women. Despite having a lower incidence of breast cancer compared to white women (124.4 compared to 127.9 per 100,000), AAs have a higher death rate (30.2 compared to 21.3 per 100,000). One explanation for this discrepancy is that breast cancer in AAs is often detected at a later stage compared to white women. We conducted this retrospective study to examine socioeconomic characteristics among AA women with breast cancer to see if there were factors associated with stage of diagnosis which may contribute to the known disparities. Methods: We identified all AA women diagnosed with any stage breast cancer from 2006-2014 within the Cleveland Clinic Cancer Data Warehouse and classified them into either early or late stage disease at time of diagnosis. Stages 0-II were classified as early and stages III-IV as late. We examined several variables at diagnosis including age, marital status, tobacco use, alcohol use, Medicaid insurance status, and breast cancer subtype which included HER-2 positive (HER+), hormone receptor positive/HER2 negative (HR+/HER-), and triple negative(TN). AA median income was obtained from US census data according to the zip code at diagnosis. We conducted univariate logistic regression for individual estimates and confidence intervals and multiple logistic regression and model selection to determine significant predictors of stage of diagnosis. Results: Of the 771 AA women identified, 108 (14%) were diagnosed at a late stage of disease with a median age of 59 years. Receptor status distribution was 12.4%, 31%, and 16.6% for HER+, HR+/HER-, and TN respectively for early stage, and 15.7%, 27%, and 25% for late stage. Among early stage 50% were current or previous smokers and 2.6% had Medicaid insurance compared to late stage patients where 63% were current or previous smokers and 9.2% had Medicaid insurance. Multiplicative effect estimates and 95% confidence intervals from univariate logistic regressions identified the following significant factors: tobacco use 1.48 [1.11-1.96] and Medicaid 3.73 [1.56-8.51] (p-values Citation Format: Winter A, Raska P, Ornstein M, Moore H, Montero A, Budd GT, Tullio K, Bailey J, Abraham J. Socioeconomic characteristics of African American women with breast cancer. [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 P1-09-03.

Background: A deeper molecular understanding of cancer biology has led to the development of therapies targeting driver mutations. Genomic profiling of tumors is commercially available and has become integrated into many clinical practices as part of a paradigm shift towards personalized care of cancer patients. The current impact of genomic profiling on clinical decision making for patients with advanced breast cancer is not well described. Methods: Patients with metastatic breast cancer (mBC) who had tumors submitted for commercial genomic analysis from 2013-2015 were identified consecutively at two large academic cancer centers with genomic basket trials open for the majority of the collection period. Demographics, tumor pathology, clinical, and treatment histories were extracted through medical chart review as per an IRB approved protocol. Data from genomic analysis reports was extracted including number and type of mutations, FDA approved therapies and clinical trials available. Genomic analysis was determined to have impacted clinical decision making if the next line of therapy was influenced either by accrual to clinical trial, or a decision to prescribe an FDA-approved therapy. The most frequent somatic mutations and their relative frequencies were determined. Results: A total of 82 patients with mBC who had undergone commercially available genomic testing were identified. The median age was 49 (range: 29-70). 42 patients (51%) had ER-positive HER2-negative disease, 33 (40%) had ER-negative HER2-negative disease, 4 (5%) had ER-negative HER2-positive disease and 3 (4%) had ER-positive HER2-positive disease. The median number of lines of therapy received prior to genomic profiling was 2 (range 0-15). Genomic analysis reports suggested that 61 (74%) of these patients had at least one FDA approved medication available for at least one somatic mutation, and 79 (96%) had at least one clinical trial available (39 (46%) in the same state, 11 (13%) in the same institution). Genomic testing influenced management in 8 patients (10%), with 6 patients (7%) experiencing a change in next line of therapy attributable to genomic information. In 74 patients (90%), genomic testing results did not affect clinical decision-making. The most frequently observed somatic mutations included: TP53, PI3KCA, MYC, CCDN1, FGF, ZNF703, GATA3, ARID1A, MCL1, PTEN, MYST3, and BRCA1. Conclusions: Genomic testing did not affect management in the vast majority of mBC patients treated at two major academic cancer centers. Furthermore, the most identified mutated genes found were not targetable. The real world clinical utility of genomic analysis remains limited in breast cancer but may influence clinical decision making in a minority of patients. Citation Format: Kruse ML, Santa-Maria CA, Raska P, Swoboda A, Jain S, Sohal D, Moore H, Budd GT, Abraham J, Montero AJ. Impact of genomic medicine on clinical decision making in patients with advanced breast cancer at two academic medical centers. [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 P4-13-24.

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .

Background Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. Methods and findings We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004–13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P

Oncotype DX recurrence score (RS) predicts risk of distant disease recurrence, and can guide chemotherapy recommendations in hormone positive, human epidermal growth factor 2-negative, early stage breast cancer. The present study aimed to evaluate the pattern of oncotype testing, RS and adjuvant treatment in patients undergoing intraoperative radiotherapy (IORT). Single center prospective data registry was queried for patients receiving IORT between October 2011 and February 2017. Patient demographics, tumor characteristics, RS, systemic therapy and recurrence information were analyzed. A total of 150 women with mean age of 70.8 years were included. The majority had invasive ductal cancer (60.6%) with 1.0 cm average tumor size and no lymph node involvement (99%). Oncotype testing was performed in 36 patients (24.3%). Low risk score (30) in one woman (3%). Patients with RS testing had significantly increased tumor sizes (1.2 vs. 1.0 cm; P

To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice. Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started. Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

Fellow in Hematology Oncology, Taussig Cancer Institute, Cleveland Clinic, 2010 E 90th St, Cleveland, OH 44195, USA Director of Breast Oncology Program, Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA *Author for correspondence: Tel.: +1 216 445 0150; Fax: +1 216 444 9464; abrahaj5@ccf.org In 2014, an estimated 232,760 women will be diagnosed with breast cancer (BC) in the USA, and approximately 40,000 will die from the disease [1]. The incidence of brain metastases (BM) from BC is approximately 5% [2,3], and the number increases to 10–16% among women with stage IV BC [4,5]. However, these figures still underestimated the disease burden, with up to 30% of BC patients found to have BM at autopsy [6,7]. Among breast cancer brain metastasis (BCBM) patients, parenchymal BM are more common than leptomeningeal involvement with the latter being reported about 5 to 16% of patients at autopsy [8]. Management of BCBM remains a clinically unmet need with few therapeutic options or clinical trials. Improvements in systemic treatment increased survival of BC patients, and unmasked a subpopulation with BM that may significantly impair patient’s life quality and survival. Unique challenges in managing BCBM patients lie in overcoming blood–brain barrier (BBB) and resistance to multiple lines of prior treatment since patients in this setting are typically pretreated [9]. Recently, better characterization of BCBM patients, development of new systemic therapy along with improvements in trial design and imaging modalities regenerated an interest in developing novel agents for BCBM patients.

Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.