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Purpose: Breast cancer mortality is higher in Black women than other racial groups. This difference has been partially attributed to a higher proportion of triple-negative breast cancer (TNBC). However, it is uncertain if survival disparities exist in racially diverse TNBC patients receiving similar treatments. Here, we examine racial differences in disease-related outcomes in TNBC patients treated on the E5103 clinical trial. Methods: From 2007 to 2011, 4,994 patients with stage I-III HER2-negative breast cancer were randomized to adjuvant chemotherapy with or without bevacizumab. This analysis was limited to the subset of 1,742 TNBC patients with known self-reported race. Unadjusted Kaplan-Meier curves and adjusted Cox-Proportional Hazards models were used to determine breast cancer events and survival outcomes. Results: Of the analysis population, 51 (2.9%) were Asian, 269 (15.4%) Black, and 1422 (81.6%) White. Median age was 51 years. Patient characteristics, treatment arm, and local therapies were similar across racial groups. White women were more commonly node-negative (56% vs. 49% and 44% in Asian and Black women, respectively; p < 0.01). At a median follow-up of 46 months, unadjusted Kaplan-Meier locoregional and distant recurrence, and disease-free and overall survival, did not differ significantly by race. In Cox models adjusted for patient and tumor characteristics and treatment arm, race was not associated with any disease event. Larger tumor size and nodal involvement were consistently associated with breast cancer events. Conclusion: This clinical trial population of similarly treated TNBC patients showed no racial differences in breast cancer outcomes. Disease extent, rather than race, was associated with disease events. [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]

Background: Racial and ethnic disparities in outcomes after treatment for ductal carcinoma in situ (DCIS) are largely unknown. The objective of this study was to examine breast cancer outcomes by race and ethnicity in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 clinical trial. Patients and Methods: The NSABP B-35 trial randomized postmenopausal women with hormone receptor-positive DCIS treated with breast-conserving therapy to 5 years of tamoxifen or anastrozole. In total, 3104 women were enrolled between 2003 and 2006. For this analysis, patients without complete self-reported race and ethnicity or with immediate trial dropout were excluded. Kaplan–Meier curves and adjusted Cox-proportional hazards models were used for analyses. Results: Of the 3061 women included, 2614 (85.4%) were non-Hispanic white (NHW), 255 (8.3%) were non-Hispanic Black (NHB), 95 (3.1%) were Hispanic, and 96 (3.1%) were Asian or Pacific Islander (API). Endocrine therapy assignment and duration were well balanced between racial and ethnic groups. Median follow-up was 9 years; unadjusted Kaplan–Meier curves did not show any racial differences in disease events. Adjusted Cox-proportional hazards models found API (versus NHW) race to be associated with higher local recurrence [hazard ratio (HzR) 2.45, p = 0.035] and NHB race to be associated with higher distant recurrence (HzR 5.03, p = 0.020) and breast cancer mortality (HzR 3.83, p = 0.046). Conclusions: Despite similar locoregional treatments and standard endocrine therapy in a clinical trial population, racial and ethnic disparities exist in long-term outcomes for hormone-receptor-positive DCIS. These findings suggest that factors outside of access and treatment may impact DCIS outcomes by race and ethnicity. [ABSTRACT FROM AUTHOR]

Background: There are limited data examining racial disparities in locoregional recurrence (LRR) among women with access to high-quality care. We aimed to examine differences in late LRR by race in patients with stage I–IIIA, hormone receptor-positive (HR+) breast cancer enrolled in the National Surgical Adjuvant Breast and Bowel (NSABP) B-42 trial. Methods: From 2006 to 2010, 3966 postmenopausal women with stage I–IIIA HR+ breast cancer who were disease-free after 5 years of endocrine therapy were randomized to an additional 5 years of endocrine therapy or placebo. Patients were excluded if multi-racial or if race was unknown. Kaplan–Meier curves were used to estimate 6-year LRR from the time of trial registration and according to race. Cox proportional hazards models were used for adjusted survival analyses. Results: Overall, 3929 NSABP B-42 patients were included: 3688 (93.9%) White, 151 (3.8%) Black, and 90 (2.3%) Asian patients. Median follow-up was 75.2 months. Overall estimated 6-year LRR from trial registration was 1.8% and differed by race: LRR rates were 1.7% in White women, 4.9% in Black women, and 0% in Asian women (p = 0.046). Adjusted Cox proportional hazards analysis found Black race to be independently associated with LRR (hazard ratio [HzR] 2.36, 95% confidence interval [CI] 1.01–5.49; p = 0.047). Node-positivity was also associated with increased LRR (HzR 1.75, 95% CI 1.07–2.86; p = 0.025). Adjusted Cox analysis found LRR (HzR 2.32, 95% CI 1.33–4.06; p = 0.003) to be associated with increased overall mortality; however, race was not independently associated with mortality. Conclusion: Among postmenopausal patients with stage I–IIIA HR+ breast cancer in the NSABP B-42 trial, racial differences in late LRR were present, with the highest LRR in Black women. [ABSTRACT FROM AUTHOR]

Opinion statement: For high-risk early-stage hormone-receptor-positive, HER2-negative breast cancer (HR + /HER2 − EBC), short- and long-term recurrence risks remain substantial despite local control with surgery and radiation and systemic treatment with chemotherapy and endocrine therapy (ET). Recent trials have provided new strategies for reducing recurrence. The monarchE trial demonstrated that adding 2 years of adjuvant abemaciclib to ET improves invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS). In the OlympiA trial for high-risk disease in patients with germline BRCA1/BRCA2 mutations, adding 1 year of olaparib to ET improved iDFS, DRFS, and overall survival (OS). In addition, for premenopausal women with high-risk tumors, long-term follow-up of the SOFT, ASTRRA, TEXT, ABCSG-12, and HOBOE trials supports the role of ovarian function suppression (OFS), in combination with adjuvant tamoxifen or aromatase inhibition (AI). For postmenopausal women with high-risk tumors, extended-duration AI for at least 7 years should be used with zoledronic acid. Given the remaining recurrence risk even with these interventions and with the ongoing development of new strategies for HR + disease, patients with high-risk EBC should be encouraged to participate in clinical trials, such as trials of immunotherapy, novel oral estrogen receptor alpha (ERα)-targeting agents, antibody–drug conjugates (ADCs), and trials guided by measurements of minimal residual disease (MRD). [ABSTRACT FROM AUTHOR]

Purpose of Review: CDK4/6 inhibition (CDK4/6i) is a key component of first-line combination treatment with endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer (HR + /HER2 − MBC). Understanding and overcoming resistance are ongoing areas of investigation. Diverse resistance mechanisms have been uncovered in cell cycle regulators and growth factor signaling components, converging on upregulation of CDK6 or on perturbation of the cell cycle downstream of CDK4/6. In this review, we discuss studies in the past few years that add new findings to this growing knowledge base. Recent Findings: Recent work has shown that CDK6 upregulation in breast cancer cells induces INK4 family members (p18INK4C and p15INK4B), which render CDK6 (but not CDK4) resistant to CDK4/6i. CDK6 can also form a CDK4/6i-resistant complex with p27KIP1 and (unlike CDK4) can sequester p21CIP1/WAF1 away from inhibiting CDK2 in the presence of CDK4/6i. These resistant complexes may be targetable by next-generation CDK4/6i such as proteolysis targeting chimeras (PROTACs). Separately, recent work has suggested that IFN-STAT1 signaling, especially over extended durations, may be a mediator of resistance rather than efficacy of CDK4/6i in breast cancer. This is based on descriptive analyses, and experiments are required to test this hypothesis. Summary: Recent research has revealed new mechanisms of CDK4/6i resistance in HR + MBC, including CDK6 complexes with INK4 and CIP/KIP members and, controversially, IFN-STAT1 signaling. Advances in these areas will inform the development of better CDK4/6 inhibitors and new combination regimens. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in the United States (US). Most patients are diagnosed with early-stage disease; however, there is still a need to prevent recurrences that often present as incurable metastatic disease. The treatment landscape of early-stage breast cancer is evolving rapidly. The immune checkpoint inhibitor pembrolizumab is approved in combination with neoadjuvant chemotherapy for the treatment of high-risk triple-negative breast cancer (TNBC). The cyclin-dependent kinase (CDK) 4 and 6 inhibitor abemaciclib is approved for adjuvant treatment of patients with high-risk hormone receptor (HR)-positive disease. While adjuvant olaparib has shown significant improvement in outcomes for patients with pathogenic/likely pathogenic BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and is approved in this setting. For the HER2-positive subtype, the post-neoadjuvant therapy can be tailored based on the response to neoadjuvant chemotherapy and HER2-targeted agents. In this narrative review, we summarize the most recent approvals for early-stage breast cancer as well as frequently encountered clinical challenges utilizing these medications. [ABSTRACT FROM AUTHOR]

Background: Guidelines support comparable treatment for women diagnosed with breast cancer during pregnancy (PrBC) and nonpregnant women with limited case-specific modifications to ensure maternal–fetal safety. Experience during pregnancy with modern agents, such as taxanes or granulocyte colony-stimulating factors (GCSF), is limited. Patients and methods: We retrospectively identified a multi-institutional cohort of PrBC between 1996 and 2020. Propensity score analyses with multiple imputation for missing variables were applied to determine the associations between chemotherapy exposures during pregnancy, with or without taxanes or GCSF, and a compound maternal–fetal outcome including spontaneous preterm birth, preterm premature rupture of membranes, chorioamnionitis, small for gestational age newborns, congenital malformation, or 5-min Apgar score < 7. Results: Among 139 PrBC pregnancies, 82 (59.0%) were exposed to chemotherapy, including 26 (31.7%) to taxane and 18 (22.0%) to GCSF. Chemotherapy use, in general, and inclusion of taxane and/or GCSF, specifically, increased over time. Pregnancies resulting in live singleton births (n = 123) and exposed to chemotherapy were as likely to reach term as those that were not (59.5% vs. 63.6%, respectively, punadjusted = 0.85). Among women treated with chemotherapy, propensity score-matched odds ratios (OR) for the composite maternal–fetal outcome were not significantly increased with taxane (OR 1.24, 95% CI 0.27–5.72) or GCSF (OR 2.11, 95% confidence interval (CI) 0.48–9.22) with similar effects in multiple imputation and sensitivity models. Conclusion: The judicious increased use of taxane chemotherapy and/or growth factor support during pregnancy was not associated with unfavorable short-term maternal–fetal outcomes. While these findings are reassuring, case numbers remain limited and continued surveillance of these patients and progeny is warranted. [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: Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides information about the frequency and severity of AEs from the provider's perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug. Methods: We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2−) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity. Results: 83 patients were enrolled: 45 into the HR+/HER2− cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24–39%) in the HR+/HER2− cohort and 13.2% (90% CI 5–26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2− disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy. Conclusions: Eribulin is active in HER2− breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs. ClinicalTrials.gov Registration: NCT01827787 [ABSTRACT FROM AUTHOR]

Background: This trial examined the efficacy of a clinic-based weight loss intervention in cancer survivors.Methods: This single-center phase II trial randomized survivors of solid tumors and hematologic malignancies to a 15-week group-based weight loss intervention that included caloric restriction and physical activity (n = 30) or a wait-list control intervention (n = 30). The primary study outcome was body mass. Secondary study outcomes included body composition using dual-energy X-ray absorptiometry, physical fitness using the 6-min walk test (6MWT), and concentrations of serum biomarkers.Results: Participants in the intervention group lost 5.6 ± 4.4% of baseline weight (4.6 ± 3.9 kg), whereas participants in the control group gained 0.2 ± 2.4% of baseline weight (0.2 ± 2.0 kg); intervention effect - 5.8% (95% CI - 7.8, - 3.8); - 4.8 kg (95% CI - 6.6, - 3.0); P = 0.0001. A larger proportion of participants in the intervention group lost ≥ 5% of baseline weight compared to the control group (43 vs 0%; P < 0.0001). The intervention led to reductions in fat mass (- 3.2 ± 0.7 kg; P < 0.0001), improvements in physical fitness (an increase of 22.6 ± 10.8 m on 6MWT; P = 0.03), and reductions in concentrations of insulin (- 7.7 ± 3.5 μU/mL; P = 0.004) and leptin (- 7.3 ± 4.0 ng/mL; P = 0.04).Conclusion: A 15-week clinic-based weight loss intervention resulted in significant weight loss and improvements in body composition, physical fitness, and concentrations of serum biomarkers in cancer survivors.Implications For Cancer Survivors: Weight loss programs provide a number of benefits for cancer survivors; survivors should inquire about the availability of lifestyle programs offered at their cancer center and within their local communities. [ABSTRACT FROM AUTHOR]

Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/ Rb interaction. Palbociclib has been studied in a randomized phase 2 clinical trial in metastatic hormone receptor positive breast cancer in which the combination of palbociclib and endocrine therapy significantly prolonged progression-free survival over endocrine therapy alone. The toxicity profile of palbociclib and the other CDK 4/6 inhibitors in early phase I and II trials has been predominantly hematologic, characterized by limited neutropenia, as well as variable gastrointestinal toxicity. Multiple phase II and III studies are ongoing with all three agents, and are designed to explore the role of CDK 4/6 inhibition in metastatic hormone receptor positive breast cancer. The next wave of studies will examine further clinical and scientific topics, including the role of CDK 4/6 inhibition in the neo/adjuvant setting, the combination of CDK 4/6 inhibitors with other targeted therapies, and the activity of CDK 4/6 inhibitors in the HER2 positive subset of breast cancer, as well as in other cancer subtypes. Should ongoing study confirm benefits and tolerability of CDK 4/6 inhibition, combination therapy with endocrine agents may become a new standard of care for hormone receptor positive breast cancer. [ABSTRACT FROM AUTHOR]

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1–8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash ( n = 2), diarrhea ( n = 2), hypoxia ( n = 1), and grade 4 pulmonary embolus ( n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59–92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring. [ABSTRACT FROM AUTHOR]

Examines the role of T-cell leukaemia oncoprotein tal-1/SCL in blood formation. Characteristics of mice lacking T-cell leukaemias; Experimental procedures; Use of reverse transcriptase-polymerase chain reaction (RT-PCR).