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Purpose: Use qualitative and quantitative methods to explore factors influencing the adoption of guideline-based physical activity (PA) and dietary recommendations among participants enrolled in a lifestyle intervention during and after chemotherapy for breast cancer. Methods: Among women with stage I-III breast cancer who participated in the intervention arm of the Lifestyle, Exercise, and Nutrition early after diagnosis (LEANer) trial, we used stratified, purposeful sampling to interview women who met both, one, or neither intervention goal after the 1-year intervention: (1) 150 min/week moderate-to-vigorous intensity exercise via a self-reported PA questionnaire and (2) improved self-reported diet quality measured by the Healthy Eating Index-2015. Semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using thematic content analysis. Results: The 29 women interviewed were 52 ± 11 years old on average, with a mean body mass index of 29.6 ± 7.7 kg/m2. Three themes emerged regarding aspects of the LEANer intervention that facilitated behavior change: (1) providing a conduit of trustworthy, timely, and personalized support and education; (2) shifting mindsets and enhanced understanding of the benefits of PA and nutrition during chemotherapy; and (3) fostering a sense of control and alternative focus. Factors described as hindering adoption of goals included: (1) adverse effects of chemotherapy and (2) competing priorities. Conclusions: Women reported the external support, tailored education, and experiencing the physical and mental benefits of the LEANer intervention facilitated the adoption of the interventions’ behavioral goals. Addressing chemotherapy-related symptoms and competing priorities may facilitate adherence to lifestyle interventions during chemotherapy for breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors. Methods: This study included participants of the Young Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments. Results: Among 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models. Conclusion: In this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors. [ABSTRACT FROM AUTHOR]

Purpose: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. Methods: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. Results: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22–13.6) on Arm A and 1.82 months (1.54–6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2–NA) on Arm A and 16.2 months (15.7–NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. Conclusion: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. ClinicalTrials.gov Identifier: NCT00083031. Date of Registration: May 17, 2004. [ABSTRACT FROM AUTHOR]

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease. Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2+ breast cancer treatment. Here, the authors develop a score that integrates antigen receptor repertoire features and clinical parameters to predict prognosis after anti-HER2 neoadjuvant treatments. [ABSTRACT FROM AUTHOR]

Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Results: Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835. [ABSTRACT FROM AUTHOR]

Background: Adding pembrolizumab to preoperative chemotherapy improves event-free survival in patients with early-stage triple-negative breast cancer (TNBC). However, owing to potential toxicities, the risk–benefit ratio of pembrolizumab must be considered. There is consensus that the addition of immunotherapy should be recommended in node-positive patients. This study is undertaken to determine nodal positivity rates in patients with TNBC presenting with cT1–2N0 disease undergoing upfront surgery and to evaluate the utility of axillary ultrasound and biopsy in the setting of a negative clinical examination. Patients and Methods: Patients with cT1–2N0 TNBC undergoing upfront surgery were identified from our institutional database (January 2016–February 2021; n = 343) and from the National Cancer Database (NCDB) (n = 46,015). Pathologic nodal status was determined. A second cohort of patients with cT1–T2 TNBC with a negative clinical examination was defined in our institutional database (n = 499), and utilization of axillary ultrasound was examined. Results: For patients undergoing upfront surgery, pathologically positive nodes were found in 14.6% patients of our institutional cohort: 9.4% cT1a/b, 14.9% cT1c, and 20.8% cT2 tumors. In the NCDB cohort, 13.7% patients were node positive: 4.9% cT1a/b, 11.4% cT1c, and 19.7% cT2 tumors. For patients with a normal clinical examination undergoing axillary ultrasound, 7.5% of cT1c and 8.7% of cT2 had suspicious nodes biopsied and confirmed positive for metastasis. Conclusions: Pathologic node-positive disease is found in > 10 and 20% patients with cT1cN0 and cT2N0 TNBC, respectively. Axillary ultrasound can be used to identify patients presenting with a normal clinical examination for whom preoperative pembrolizumab should be considered. [ABSTRACT FROM AUTHOR]

Background: The American Joint Committee on Cancer (AJCC) 8th edition pathologic prognostic staging (PPS) incorporates anatomic and biologic factors. The OncotypeDX Breast Recurrence Score (RS) was included based on the initial report of the TAILORx trial, with T1-2N0 hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer patients who had a RS < 11 staged as PPS 1A. This study examined whether the RS criteria for PPS 1A can be further expanded using patients enrolled in the TAILORx trial. Methods: The TAILORx trial enrolled 10,273 HR+HER2− T1-2N0 patients. Those with incomplete HR-status/grade and T3 disease were excluded for analysis. The recurrence-free interval (RFI) was compared between the patients who did and those who did not fall into the current PPS 1A category using the Kaplan-Meier method. Results: The study enrolled 9535 patients for analysis. The RS was < 11 in 16.1%, 11–17 in 35.9%, 18–25 in 32.4%, and > 25 in 15.6% of the patients. The majority (91.2%) of the patients (including all the T1N0 patients regardless of RS) were PPS 1A, and 8.8% were not-PPS 1A. The median follow-up time was 95 months. The PPS 1A patients had an 8-year RFI of 94.2%, which was similar to that of the patients with a RS of 11–17 who were not-PPS 1A (91.7%; p = 0.07) and better than that of the patients with a RS ≥ 18 who were not-PPS 1A (85.4% for a RS of 18–25, 76.0% for a RS > 25; both p < 0.01). Similar RFI trends were seen in patients who received endocrine therapy or chemotherapy followed by endocrine therapy. Conclusions: Patients with T1-2N0 HR+HER2− breast cancer and a RS < 18 have an RFI similar to that of patients staged as PPS 1A by the current AJCC staging system, regardless of treatment, suggesting that the criteria for PPS 1A can be expanded to include a RS < 18. [ABSTRACT FROM AUTHOR]

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM. [ABSTRACT FROM AUTHOR]

Purpose: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II–III breast cancer. Methods: Tumor cells from patients with metastatic (n = 15) and stage II–III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II–III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II–III). Results: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4–13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II–III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells. Conclusion: We conclude that tumor cells can be harvested from patients with metastatic or stage II–III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. Trial registration and date of registration: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009). [ABSTRACT FROM AUTHOR]

PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer. PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism. [ABSTRACT FROM AUTHOR]

Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16INK4A is deficient in the majority of HER2+ BCBMs. p16INK4A-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM. HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug. [ABSTRACT FROM AUTHOR]

Purpose: To compare the impact of exercise and mind–body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer. Methods: The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind–body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models. Results: Mind–body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind–body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind–body: average change = -2.59, p = 0.05, d = 0.29), while mind–body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67). Conclusions: Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind–body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer. Trial registration: ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012. [ABSTRACT FROM AUTHOR]

Purpose: We sought to understand the attitudes of individuals with abnormal breast imaging findings prompting a diagnostic breast biopsy toward donation of blood, excised tissue, or percutaneous biospecimens for research, and to understand medical oncologists' attitudes toward research biospecimen collection in this population. Methods: We included individuals who presented to a single academic medical center for a clinically indicated, image-guided, percutaneous breast biopsy. We administered a survey prior to knowledge of biopsy results to assess willingness to consider, entirely for research purposes, donating blood or excess excised breast tissue, or having additional biospecimens (AB) obtained during a clinically indicated percutaneous biopsy. We also surveyed breast medical oncologists from National Cancer Institute-designated cancer centers to assess attitudes toward approaching patients for biospecimen research. Results: Overall, 53/63 patients responded to the survey; 70% would consider donating blood, 85% would consider donating excess excised breast tissue, and 32% would consider having AB obtained during a clinically indicated biopsy. Main motivating factors for considering AB included contributing to scientific knowledge and return of study or biopsy results, whereas anxiety and the potential discomfort were the main dissuading factors. Among 191 medical oncologists, most were very comfortable (59.2%), or somewhat comfortable (32.5%) asking patients to have AB obtained during a clinically indicated breast biopsy. Medical oncologists reported hesitancy to refer a patient for AB due to potential pain/discomfort, and other procedure risks. Conclusions: Only one-third of individuals with breast imaging findings would consider consenting to AB during a diagnostic biopsy, whereas most were open to donating blood or excess excised breast tissue. Most medical oncologists would be comfortable asking patients to have AB obtained during the biopsy. Understanding patients' and oncologists' baseline attitudes may inform the design and approach to breast biospecimen-based research. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the efficacy and safety of poly-(adenosine diphosphate-ribose) polymerase (PARP) 1 and 2 inhibitor veliparib and temozolomide in metastatic breast cancer patients with and without germline BRCA1/2 mutations. Methods: In this single-arm phase II trial, patients with metastatic breast cancer received veliparib 30 to 40 mg twice daily on days 1 to 7 with concurrent temozolomide 150 mg/m2 on days 1 to 5 of a 28-day cycle. The primary cohort was unselected for BRCA mutation status, and an expansion cohort enrolled only BRCA1/2 carriers. The primary endpoint was objective response rate (ORR) in each cohort. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and evaluation of safety and tolerability. Results: In the primary cohort of 41 unselected patients, which included 9 BRCA mutation carriers, the ORR was 10% and clinical benefit rate at 4 months (CBR) was 27%. In the expansion cohort of 21 BRCA1/2 carriers, the ORR was 14% and CBR was 43%. Among all 30 BRCA1/2 carriers, the ORR was 23% versus 0% among non-carriers. In the subset of BRCA1/2 carriers, the ORR was 32% among platinum-naïve patients versus 9% among platinum-exposed patients. The median PFS was 3.3 months among BRCA1/2 carriers compared to 1.8 months among non-carriers (HR: 0.48, p = 0.006). A longer median PFS of 6.2 months was observed among BRCA1/2 carriers who had no prior platinum therapy. The most common grade 3 and 4 toxicities were thrombocytopenia (32%) and neutropenia (21%) that generally improved with dose modifications. Conclusion: Veliparib and temozolomide demonstrated clinical activity in platinum-naïve BRCA-associated metastatic breast cancer with manageable toxicity at doses of veliparib well below the single-agent active dose. Although the study did not meet its primary endpoint in unselected nor BRCA-associated breast cancer, this regimen was further evaluated in the BROCADE 2 study. Trial registration: NCT01009788 (ClinicalTrials.gov), November 9, 2009 [ABSTRACT FROM AUTHOR]

Purpose: Most reports describing the risk of late relapse in breast cancer (BC) have been based on selected patients enrolled into clinical trials. We examined population-based long-term risks of BC-specific mortality (BCSM), the risks of BCSM conditional on having survived 5 years, and factors associated with late BCSM. Methods: Using SEER, we identified women diagnosed with BC (T1-T2, N0-N2, M0) between 1990 and 2005 with known hormone receptor (HR) status. Kaplan–Meier analyses determined cumulative risks of BCSM. We performed Fine and Gray regression stratified by HR status. Results: We included 202,080 patients (median follow-up of 14.17 years). Of all BC deaths, the proportion that occurred after 5 years was 65% for HR-positive vs 28% for HR-negative (p < 0.001) BC. In HR-positive BC, the cumulative risks of BCSM during years 5–20 were 9.9%, 21.9%, and 38% for N0, N1, and N2 disease. For HR-negative BC, the risks were 7.9%, 12.2%, and 19.9%, respectively. For T1a/b, N0, HR-positive BC, the risk of BCSM was 6 times lower than the risk of non-BCSM. In N2, HR-positive BC, the risk of BCSM was 43% higher than the risk of non-BCSM. In adjusted Fine and Gray models stratified by HR status, the risks of BCSM conditional on having survived 5 years for both HR-positive and HR-negative depended on T-N status, age, and year of diagnosis. In HR-positive, the risks also depended on race and grade. Conclusion: The risks of BCSM beyond 5 years, although different, remain important for both HR-positive and HR-negative BC. Strategies to prevent early and late recurrences are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Male breast cancer is an uncommon disease, and population-based information regarding prognostic factors is limited. Most cases are hormone receptor (HR) positive; however, the association of tumor subtype with overall survival (OS) and breast cancer-specific survival (BCSS) is unclear. Methods: Using SEER data, we identified men with invasive breast cancer between 2010 and 2017 with known HR and HER2 status. We examined tumor subtypes by patient characteristics and performed multivariate Cox proportional hazards analyses to determine the associations of each variable with OS and BCSS. Results: We included 2389 men with a median follow-up of 43 months (IQR 19–68). Median age was 66 years. Tumor subtype distribution was 84.1% HR+/HER2−, 12.7% HR+/HER2+ , 0.8% HR−/HER2+, and 2.3% triple-negative (TN). In univariate analysis, OS at 5 years was 76.5% for HR+/HER2−, 65.1% for HR+/HER2+ , 84.2% for HR-/HER2+, and 48.1% for TN (p < 0.0001). Of all subtypes, TN had the worst BCSS (p < 0.0001). Stage, tumor subtype and race were significantly associated with OS and BCSS in multivariate analysis. Adjusted Cox hazard ratios for OS by tumor subtype with HR+/HER2− as reference were 1.55 for HR+/HER2+ (p = 0.001), 1.1 for HR−/HER2+ (p = 0.888), and 3.59 for TN (p < 0.001). Conclusion: We observed significant differences in survival outcomes by tumor subtype. Poor outcomes among men with HER2+ and TN disease suggest possible under-treatment, aggressive tumor biology, and/or more advanced disease at presentation. Studies to better understand the inferior survival for men with these subtypes are warranted and will likely require international collaboration. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to report the 20-year risk of breast cancer-specific mortality (BCSM), report the risk of BCSM conditional on having survived 5 years, and identify factors associated with late deaths in stage III breast cancer. Methods: Using Surveillance, Epidemiology, and End Results data, we included women with stage III breast cancer diagnosed from 1990 to 2005. We excluded women with unknown hormone receptor (HR) status, women who did not undergo resection of the primary tumor or axillary nodes, or unknown cause of death. We estimated risks of BCSM using cumulative incidence function and used Fine and Gray regression to identify factors associated with late deaths. Results: Final sample was 36,500 patients with 14 years of median follow-up. For each stage subgroup, the risk of BCSM at 20 years was significantly higher for HR-negative vs HR-positive tumors (IIIA: 49.8% vs 43.2%, P < 0.0001; IIIB: 60.9% vs 47.6%, P < 0.0001; IIIC: 68.7% vs 63.1%, P < 0.0001). Compared with the risks of non-BCSM, the risks of BCSM at 20 years were four times higher in stage IIIC HR-positive disease and seven times higher in stage IIIC HR-negative disease. Risks of BCSM conditional on having survived 5 years depended on tumor size, nodal status, race, and tumor grade for HR-positive disease and depended on tumor size, nodal status, and age for HR-negative disease. Conclusions: In stage III breast cancer, the risk of BCSM at 20 years is very high and remains important even beyond the first 5 years in both HR-positive and HR-negative disease. Late BCSM depends on traditional clinicopathologic factors. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical studies support the JAK2–STAT3 signaling pathway as a key driver in CD44+ CD24− "stem-cell-like" breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Methods: Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10–25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D. Results: Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1–12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response. Conclusion: The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429). Trial registration: NCT02041429. Date of registration: January 22, 2014. [ABSTRACT FROM AUTHOR]

Purpose: The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2−) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT). Methods: We identified patients with stage I–III ER+/HER2− BC treated with NCT from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling. Results: 76 women received NCT for ER+/HER2− BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24–40). Scores ranged between 5 and 77 with 50% >25 and 5% <11. Median Recurrence Score result was significantly higher among tumors achieving pCR vs. non-pCR response (61.5 vs. 23, pwilcoxon = 0.0005). pCR rate in patients with scores >25 was 21% (8/38) vs. 5% in patients with scores <25 (2/38) (p = 0.09), with both pCRs in the <25 group in patients with scores between 21 and 25. In multivariable analysis, only Recurrence Score result was significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01). Conclusions: In young women with ER+/HER2− BC who received NCT, higher pretreatment Recurrence Score result was associated with an increased likelihood of pCR. Gene expression profile assays may have a role in decision making in young women in need of neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Purpose: In 2016, we initiated standardized "reflex" Oncotype DX Recurrence Score (RS) testing for patients ≤ 65 years with pT1-2N0-1 HR+/HER2− breast cancer. Here, we examine RS testing patterns, RS distribution, and factors associated with chemotherapy use in patients with pN1 breast cancer. Methods: Patients with stage I–III HR+/HER2− pN1 breast cancer treated with upfront surgery from February 2016 to March 2019 were identified. Clinical characteristics were compared between patients meeting reflex RS testing criteria, those with RS ordered outside of reflex criteria, and those without RS testing. RS was categorized as low (< 18), intermediate (18–30), and high (≥ 31). Multivariate logistic regression was performed to identify factors associated with adjuvant chemotherapy receipt. We examined 3-year recurrence-free survival (RFS) and overall survival (OS) stratified by chemotherapy use. Results: We identified 347 HR+/HER2− pN1 patients; 272 (78.4%) received RS testing, and 194 (71.3%) met reflex criteria. RS was < 18 in 164 (61.4%) patients, 18–30 in 89 (32.7%) patients, and ≥ 31 in 16 (5.9%) patients. On multivariate analysis, RS < 18 (OR 0.47, 95% CI 0.24–0.92) was associated with lower odds of chemotherapy use, whereas presence of lymphovascular invasion (OR 1.77, 95% CI 1.03–3.07) and lobular subtype (OR 2.40, 95% CI 1.21–4.78) were associated with higher odds. No differences in 3-year RFS (p = 0.97) or OS (p = 0.19) based on chemotherapy receipt were observed. Conclusion: Most RS-tested HR+/HER2− pN1 patients at our center had low genomic risk. A low RS independently influenced chemotherapy omission and in RS-tested patients, short-term outcomes were excellent. Our study demonstrates increased use of RS in guiding adjuvant treatment decisions in node-positive disease. [ABSTRACT FROM AUTHOR]

Purpose: 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). Methods: 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. Results: 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. Conclusions: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. Trial registration: Clinicaltrial.gov registration: NCT02260531. [ABSTRACT FROM AUTHOR]

Purpose: 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). Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer.Methods: CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined.Results: One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events.Conclusions: Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring. [ABSTRACT FROM AUTHOR]

The paradigm of targeted therapy was pioneered for chronic myeloid leukemia (CML). The advent of tyrosine kinase inhibitors (TKIs) has led to marked improvements in responses and overall survival; however, there is still a subset of patients that are either resistant through a multitude of mechanisms or intolerant to standard TKI therapy. Omacetaxine mepesuccinate (omacetaxine), a semisynthetic purified homoharringtonine compound, has been studied for over 40 years and was approved in 2012 by the Food and Drug Administration (FDA) for patients with CML refractory or intolerant to two or more TKIs. Omacetaxine has a novel mechanism of action—inhibition of protein synthesis, which does not overlap with kinase inhibition. Multiple studies have demonstrated that omacetaxine can achieve responses in heavily treated patients with either chronic-phase or accelerated-phase CML, regardless of the presence of mutations in the tyrosine kinase domain. This review will outline the tortuous story of omacetaxine, including preclinical and clinical studies of homoharringtonine, current indications, and management guidelines. [ABSTRACT FROM AUTHOR]

Purpose 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. Methods 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. Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Purpose: Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65 years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. Patients and methods: Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24 months post-entry. Results: Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number = 3) and 64% (median number = 1) of patients post-operatively and at 24 months. At 24 months 2% had persistence of six MEs. Seventy-four percent experienced at least ≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. Conclusion: Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL. [ABSTRACT FROM AUTHOR]

In this phase 2 study, patients with solid tumors receiving gemcitabine monotherapy or gemcitabine plus cisplatin/carboplatin were randomized 2:1 to eltrombopag 100 mg ( n = 52) or placebo ( n = 23) for 5 days before and after chemotherapy was started. The primary endpoint was prechemotherapy (Day 1) platelet count across ≤6 cycles. Prechemotherapy platelet counts were numerically higher with eltrombopag than placebo. Frequencies of grades 3/4 thrombocytopenia were lower with eltrombopag in both the combination therapy (77 vs. 100%) and monotherapy (36 vs. 42%) groups. Proportionately fewer eltrombopag-treated patients had platelet counts <100 × 10/L at nadir. Among patients receiving combination chemotherapy, mean time to recovery from platelet nadir was 8 days with eltrombopag vs. 15 days with placebo. Eltrombopag-treated patients had fewer dose delays/reductions or missed doses due to thrombocytopenia in both the combination therapy (77 vs. 91%) and monotherapy (62 vs. 83%) groups. Adverse events and serious adverse events were less frequent with eltrombopag in both chemotherapy groups, with reduced rates of anemia, neutropenia, and thrombocytopenia in patients receiving combination chemotherapy. In conclusion, eltrombopag treatment shortened the time to recovery from platelet nadir in patients treated with gemcitabine-based chemotherapy and reduced dose delays/reductions due to thrombocytopenia. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score ≥8 or score ≥12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291 [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer patients aged 65+ ('older') vary in frailty status. We tested whether a deficits accumulation frailty index predicted long-term mortality. Methods: Older patients ( n = 1280) with non-metastatic, invasive breast cancer were recruited from 78 Alliance sites from 2004 to 2011, with follow-up to 2015. Frailty categories (robust, pre-frail, and frail) were based on 35 baseline illness and function items. Cox proportional hazards and competing risk models were used to calculate all-cause and breast cancer-specific mortality for up to 7 years, respectively. Potential covariates included demographic, psychosocial, and clinical factors, diagnosis year, and care setting. Results: Patients were 65-91 years old. Most (76.6%) were robust; 18.3% were pre-frail, and 5.1% frail. Robust patients tended to receive more chemotherapy ± hormonal therapy (vs. hormonal) than pre-frail or frail patients (45% vs. 37 and 36%, p = 0.06), and had the highest adherence to hormonal therapy. The adjusted hazard ratios for all-cause mortality ( n = 209 deaths) were 1.7 (95% CI 1.2-2.4) and 2.4 (95% CI 1.5-4.0) for pre-frail and frail versus robust women, respectively, with an absolute mortality difference of 23.5%. The adjusted hazard of breast cancer death ( n−99) was 3.1 (95% CI 1.6-5.8) times higher for frail versus robust patients (absolute difference of 14%). Treatment differences did not account for the relationships between frailty and mortality. Conclusions: Most older breast cancer patients are robust and could consider chemotherapy where otherwise indicated. Patients who are frail or pre-frail have elevated long-term all-cause and breast cancer mortality. Frailty indices could be useful for treatment decision-making and care planning with older patients. [ABSTRACT FROM AUTHOR]

Purpose: Tools to estimate survival, such as ePrognosis (), were developed for general, not cancer, populations. In older patients with breast cancer, accurate overall survival estimates would facilitate discussions about adjuvant therapies. Methods: Secondary analyses were performed of data from two parallel breast cancer studies (CALGB/Alliance 49907/NCT000224102 and CALGB/Alliance 369901/NCT00068328). We included patients ( n = 971) who were age 70 years and older with complete baseline quality of life data (194 from 49907; 777 from 369901). Estimated versus observed all-cause two-year mortality rates were compared. ePrognosis score was calculated based on age, sex, and daily function (derived from EORTC QLQ-C30). ePrognosis scores range from 0 to 10, with higher scores indicating worse prognosis based on mortality of community-dwelling elders and were categorized into three groups (0-2, 3-6, 7-10). Observed mortality rates were estimated using Kaplan-Meier methods. Results: Patient mean age was 75.8 years (range 70-91) and 73% had stage I-IIA disease. Most patients were classified by ePrognosis as good prognosis ( n = 562, 58% 0-2) and few ( n = 18, 2% 7-10) poor prognosis. Two-year observed mortality rates were significantly lower than ePrognosis estimates for patients scoring 0-2 (2% vs 5%, p = 0.001) and 3-6 (8% vs 12%, p = 0.01). The same trend was seen with scores of 7-10 (23% vs 36%, p = 0.25). Conclusions: ePrognosis tool only modestly overestimates mortality rate in older breast cancer patients enrolled in two cooperative group studies. This tool, which estimates non-cancer mortality risk based on readily available clinical information may inform adjuvant therapy decisions but should be validated in non-clinical trial populations. [ABSTRACT FROM AUTHOR]

Purpose: Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT). Methods: Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS). Results: Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage. Conclusions: In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control. [ABSTRACT FROM AUTHOR]

Objective: It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). Methods: The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). Results: Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. Conclusions: Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed. [ABSTRACT FROM AUTHOR]

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 OR = 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Breast-conserving surgery (BCS) provides equivalent survival outcomes to unilateral mastectomy. There is no survival advantage to bilateral mastectomy in average risk breast cancer. Among a cohort of breast cancer patients expected to be candidates for BCS, we examined choice of surgery and factors associated with it. A prospective cohort study of unilateral clinical Stage I breast cancer patients treated at National Comprehensive Cancer Network centers from 2000 to 2009 was performed. The proportion of patients who initially underwent mastectomy versus BCS and time to definitive surgery and chemotherapy were examined. Of 10,249 patients, 23 % underwent mastectomy as an initial surgery. No decline in the use of mastectomy as initial surgery was found. There was significant institutional variation, with rates of initial mastectomy ranging from 14 to 30 % (adjusted odds ratio: 0.42-1.38). Tumor characteristics were associated with surgical option, but with small absolute differences. Of those who received initial mastectomy, 22 % had bilateral mastectomy, with an increase over time (2000:13 % vs. 2009:30 %) and substantial institutional variation (11-34 %). Women treated with initial mastectomy had longer median times from diagnosis to complete definitive surgery (6 vs. 4 weeks) and to start of adjuvant chemotherapy (12 vs. 11 weeks). Among Stage I breast cancer, the overall use of mastectomy did not change significantly over 10 years; however, an increasing proportion of women with unilateral cancer had bilateral mastectomy, and there was wide variation in type of surgery by institution. Further studies to assess reasons for the observed wide variation are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Recent consensus guidelines on margins for breast-conserving surgery (BCS) recommend the use of 'no ink on tumor' as the standard for an adequate margin. The recommendations extend to invasive lobular carcinoma (ILC), but the data on this subset are limited. We reviewed our modern dataset on margin status with outcomes of ILC. Methods: We performed a retrospective cohort study on 736 patients with a diagnosis of stage I-III ILC treated at our cancer center between May 1997 and December 2007. Clinicopathologic data were extracted from the Clinical Research Information Systems Database. Margin status was defined using the latest ASCO/ASTRO/SSO consensus guideline criteria. Results: The initial surgery performed was mastectomy in 352 patients (48 %) and BCS in 384 patients (52 %). In multivariate analysis, tumor size and multifocality were significantly associated with high rates of mastectomy and positive surgical margins at initial BCS. After initial BCS, additional surgery was performed in 92 patients (24 %). During a 72-month median follow-up period, 12 (3.1 %) ipsilateral breast tumor recurrences (IBTR) and 5 (1.3 %) other locoregional recurrences (LRR) were observed. Patients with margins with ink on tumor who did not receive further surgery were found to have significantly increased LRR [odds ratio (OR) 5.5; p = 0.02] and IBTR (OR 8.5; p = 0.006), whereas patients with close margins (1-3 mm) and margins within 1 mm were not. Conclusions: Our study supports the validity of using 'no ink on tumor' as the standard for a negative margin for pure and mixed ILC treated with multimodality therapy. [ABSTRACT FROM AUTHOR]

Opportunistic infection with Pneumocystis jiroveci pneumonia (PCP) has not been recognized as a significant complication of early-stage breast cancer treatment. However, we have observed an increase in PCP incidence among patients receiving chemotherapy for early-stage breast cancer. Herein we identify risk factors for and calculate incidence of PCP in this population. We identified all cases of PCP at Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) from 1/1/2000 to 12/31/2013 in patients with stage I-III breast cancer treated with an adriamycin/cyclophosphamide (AC)-containing regimen. Nineteen cases of PCP in non-metastatic breast cancer patients were identified. All patients with PCP were diagnosed after receipt of either three or four cycles of AC chemotherapy on a dose-dense schedule. Patients who developed PCP were treated with median 16.4 mg prednisone equivalents/day as nausea prophylaxis for a median 64 days. The overall incidence of PCP among 2057 patients treated with neoadjuvant or adjuvant dose-dense AC for three or more cycles was 0.6 % (95 % confidence interval 0.3-1.0 %). No PCP was diagnosed in 1001 patients treated with non-dose-dense AC. There was one death from PCP. Women receiving dose-dense AC chemotherapy for early-stage breast cancer are at risk for PCP. Administering the same chemotherapy and corticosteroid dose over an 8-week versus 12-week non-dose-dense schedule appears to have created a novel infectious vulnerability. Replacing dexamethasone with alternative anti-emetics may mitigate this risk. [ABSTRACT FROM AUTHOR]

Background: Rates of contralateral prophylactic mastectomy (CPM) have increased in the United States, with younger women with breast cancer the most likely to have CPM. Methods: As part of an ongoing cohort study of young women diagnosed with breast cancer at age ≤40 years, we conducted multinomial logistic regression of data from 560 women with unilateral Stage I-III disease to identify factors associated with: (1) CPM versus unilateral mastectomy (UM); (2) CPM versus breast-conserving surgery (BCS). Results: Median age at diagnosis was 37 years; 66 % of women indicated that their doctor said that BCS was an option or was recommended. Of all women, 42.9 % had CPM, 26.8 % UM, and 30.4 % BCS. Among women who said the surgical decision was patient-driven, 59.9 % had CPM, 22.8 % BCS, and 17.3 % UM. Clinical characteristics associated with CPM versus BCS included HER2 positivity, nodal involvement, larger tumor size, lower BMI, parity, and testing positive for a BRCA mutation. Emotional and decisional factors associated with CPM versus UM and BCS included anxiety, less fear of recurrence, and reporting a patient-driven decision. Women who reported a physician-driven decision were less likely to have had CPM than both of the other surgeries, whereas higher confidence with the decision was associated with having CPM versus BCS. Conclusions: Many young women with early-stage breast cancer are choosing CPM. The association between CPM and emotional and decisional factors suggest that improved communication together with better psychosocial support may improve the decision-making process. [ABSTRACT FROM AUTHOR]

Background MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Methods Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. Results 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). Conclusion This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy. [ABSTRACT FROM AUTHOR]

Background: Accurate risk stratification is necessary for epidemiologic and outcomes research in diffuse large B-cell lymphoma (DLBCL). We evaluated performance characteristics of the clinically derived International Prognostic Index (IPI) and revised IPI (R-IPI) with a regression model-based score using the National Cancer Data Base.Methods: We studied DLBCL patients diagnosed in 2004-2011, divided into derivation and validation cohorts. The model-based score was calculated from a Cox model incorporating variables routinely recorded by cancer registries. Calibration and discrimination of the indices with regard to overall survival were evaluated in the validation cohort.Results: The IPI was recorded in 19,511 of 119,942 patients, of whom 79 % received chemotherapy. Both clinical indices provided good survival discrimination (5-year estimate range 33-74 % for the IPI, and 41-87 % for the R-IPI), but explained only 16 % of variation in survival. Survival predictions among chemotherapy-treated patients were similar to estimates from published clinical cohorts. The model-based score had significantly better discrimination characteristics (5-year survival estimate range 22-87 %) and explained 23 % of variation in survival.Conclusions: We validated the IPI and R-IPI as recorded by cancer registries to provide robust risk stratification in the general population with DLBCL, but a prognostic model using raw registry data provides superior performance. Explicit recording of prognostic factors is preferable to abstracting coarsened clinical indices for the purpose of population-based epidemiologic research. Considering low variation of survival explained by the standard clinical variables, incorporating molecular markers into registry data is necessary to improve risk stratification. [ABSTRACT FROM AUTHOR]

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients []. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms. [ABSTRACT FROM AUTHOR]

Treatment advances have differed by breast cancer subtype. We examined the impact of race on survival of women with metastatic breast cancer by disease subgroup. Using surveillance, epidemiology, and end results -Medicare data, we included white and black patients aged ≥66 with de novo metastatic breast cancer diagnosed between 1998 and 2009. Using trastuzumab as a proxy for human epidermal growth factor receptor 2 (HER2)-positive status, we defined three disease subgroups: (1) HER2-positive (received trastuzumab), (2) HER2-negative/unknown (never received trastuzumab)/hormone receptor (HR)-positive, and (3) HER2-negative/unknown/HR-negative. Multivariate Cox proportional models assessed the impact of race on overall survival (OS) and breast cancer-specific survival by subgroup. We also examined trastuzumab treatment patterns. Among 4364 women (86 % white, 14 % black), 9 % had HER2-positive, 72 % had HER2-negative/unknown/HR-positive, and 18 % had HER2-negative/unknown/HR-negative tumors. Patients with HER2-positive disease experienced longer median OS compared with others: 2.4 versus 1.8 years for women with HER2-negative/unknown/HR-positive and 0.5 years for women with HER2-negative/unknown/HR-negative disease ( P < 0.001). Racial differences in OS were only observed among patients with HER2-positive tumors: median OS: 1.4 versus 2.7 years for black and white women, adjusted hazard ratio 1.45; 95 % Confidence interval 1.01-2.08. Results for breast cancer-specific survival were similar. We also observed racial differences in trastuzumab utilization, with longer median time to trastuzumab initiation and lower likelihood of continuation over time for black (vs. white) patients. Among women with de novo metastatic breast cancer, racial differences in survival were only apparent for those with inferred HER2-positive tumors. Further study of how treatment patterns affect outcomes is warranted. [ABSTRACT FROM AUTHOR]

This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm. [ABSTRACT FROM AUTHOR]