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Opinion statement: Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased risk for the development of systemic and brain metastases. However, the advent of trastuzumab and more recently several other HER2-targeting novel therapies has led to significant improvements in the prognosis, making the diagnosis a "double-edged sword." The current standard first-line therapy for patients with HER2+ metastatic breast cancer (MBC) is a taxane combined with trastuzumab and pertuzumab. Trastuzumab deruxtecan should be used preferentially in the second line, with the only caveat being patients with CNS involvement where the tucatinib, capecitabine, and trastuzumab regimen could be considered. In the third line setting, given the survival benefits demonstrated with the tucatinib regimen in patients with and without CNS metastases, this is the preferred strategy. In the fourth line and beyond, there is no clear standard. Options include margetuximab in combination with chemotherapy, neratinib + capecitabine, or trastuzumab + chemotherapy. There are several novel therapies under investigation reporting promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, with several active therapies being moved to the early-stage setting. Accordingly, it will be critical to identify biomarkers and mechanisms of resistance to optimize therapy selection and maximize patient outcomes and quality of life. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer and address the specific scenarios which may impact treatment selection including triple-positive breast cancer and the presence of brain metastases. Finally, we highlight promising novel treatments and ongoing trials that may impact future treatment sequencing. [ABSTRACT FROM AUTHOR]

Introduction: Genetic mutations in breast cancer susceptibility gene 1 or 2 (BRCA1/2) confer a high risk for developing breast cancer; however, at least 50% of women with BRCA1/2 mutations go undiagnosed. This study evaluated differences in patient demographics, clinical characteristics, and BRCA1/2 mutation testing in the USA, European Union (EU4), and Israel in a real-world population of patients with human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). Methods: This study was a retrospective analysis of data from the Adelphi Real World ABC Disease Specific Programme in the USA, EU4, and Israel. Medical oncologists completed a patient record form, which included detailed questions on demographics, clinical assessments and outcomes, and treatment history. Eligible patients were at least 18 years of age and receiving therapy for stage IIIb–IV ABC. Results: Among the 2527 study patients, 407 were from the USA, 1926 were from the EU4, and 194 were from Israel; 86% had hormone receptor–positive (HR+)/HER2− ABC and 14% had triple-negative breast cancer (TNBC). Israeli patients had a higher rate of family history of BRCA-related cancer (69%) compared with patients in the EU4 (18%; p < 0.0001) and USA (18%; p < 0.0001). Among patients with HR+/HER2− ABC, the BRCA1/2 testing rate was 99% in Israel, 37% in the EU4, and 68% in the USA (p < 0.0001 vs Israel and the EU4). The age of tested patients was significantly younger in Israel (56 years) compared with the EU4 (59 years; p = 0.016 vs Israel) and USA (64 years; p < 0.0001 vs Israel and the EU4). Among patients with TNBC, the BRCA1/2 testing rate was 100% in Israel, 78% in the EU4 (p < 0.0001 vs Israel), and 93% in the USA (p < 0.002 vs the EU4). Among tested patients, genetic counseling rates were also higher in Israel (98%) compared with the EU4 (40%; p < 0.0001) and USA (38%; p < 0.0001). Conclusions: Testing and genetic counseling rates for BRCA1/2 mutations were very high in Israel, potentially due to the high rate of family history of BRCA-related cancer in this population and higher general awareness of genetic testing. In the EU4 and USA, overall rates of testing for BRCA1/2 mutations and genetic counseling were significantly lower compared with Israel. Given the high risk of breast cancer in BRCA1/2 mutation carriers and the efficacy of new therapies in treating ABC with a BRCA1/2 mutation, efforts should be made to improve BRCA1/2 testing rates in Europe and the USA. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the incidence of febrile neutropenia (FN) and related clinical outcomes among patients treated with myelosuppressive chemotherapy for nonmyeloid malignancies who received pegfilgrastim on-body injector (OBI) or other options (Other) for FN prophylaxis. Methods: In this prospective observational study, adult patients with breast, prostate, or lung cancer, or non-Hodgkin lymphoma at risk for FN were stratified into subgroups based on FN prophylaxis used in the first chemotherapy cycle: pegfilgrastim OBI vs Other (pegfilgrastim or biosimilar pegfilgrastim prefilled syringe, daily filgrastim, or no granulocyte colony–stimulating factor [G-CSF]) for up to 4 planned chemotherapy cycles. Results: This US study enrolled 2575 eligible patients (OBI, 1624; Other, 951). FN incidence was lower in the OBI group (6.4% [95% CI, 5.2–7.6%]) than in the Other group (9.4% [7.5–11.2%]), with a relative risk (RR) of 0.66 (0.47–0.91; p =.006). A decreased risk of dose delays among patients receiving pegfilgrastim OBI vs Other was observed (RR for ≥ 5 days: 0.64 [0.42–0.96], p =.023; RR for ≥ 7 days: 0.62 [0.40–0.91], p =.016). Adherence, defined as G-CSF support for all chemotherapy cycles, was 94.0% (92.9–95.2%) in the OBI group compared with 58.4% (55.2–61.5%) in the Other group. Compliance with pegfilgrastim, defined as administration the day after chemotherapy, was 88.3% in the OBI group and 48.8% in the prefilled syringe group. Conclusion: Patients receiving pegfilgrastim OBI had a lower incidence of FN compared with those receiving alternatives. The OBI was associated with improved adherence to and compliance with clinically recommended G-CSF prophylaxis. [ABSTRACT FROM AUTHOR]

Purpose: Genomic profiling in early-stage breast cancer provides prognostic and predictive information. Genomic profiling assays have not been validated in locally advanced breast cancer (LABC). We examined a large cancer registry to evaluate genomic profiling in LABC and its effect on treatment decisions and survival. Methods: Females with ER+/HER2− LABC who did not receive neoadjuvant therapy were selected from the National Cancer Database 2004–2017. We compared characteristics between patients with and without genomic profiling and with low genomic risk, 21-gene recurrence score ≤ 25 or low-risk 70-gene signature, treated with endocrine therapy ± chemotherapy. Propensity score methods were utilized to account for covariates that may have predicted treatment. Univariable and multivariable survival analyses were performed. Results: Of 18,437 patients with LABC, 1258 (7%) had genomic profiling and 1022 (81%) had low genomic risk results. 562 patients (55%) with low genomic risk received chemotherapy and endocrine therapy (chemoendocrine). Patients who received chemoendocrine therapy were younger, had fewer comorbidities, presented with higher stage disease, had higher grade tumors, more frequently had partial mastectomy, and more often received radiation than those who received endocrine therapy alone. On multivariable analysis, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy (HR 1.77, 95% CI 1.13–2.78, p = 0.013). Conclusion: In women with LABC and low genomic risk, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy. This suggests that genomic profiling is not predictive in LABC. Accordingly, genomic profiling should not be routinely utilized to make adjuvant treatment decisions in LABC in the absence of further data which shows a benefit. [ABSTRACT FROM AUTHOR]

Background: Breast cancer chemotherapy often carries a high risk of febrile neutropenia (FN); guidelines recommend prophylaxis with granulocyte colony-stimulating factor (G-CSF), such as pegfilgrastim. Neulasta® Onpro® on-body injector (OBI) is a delivery device administering pegfilgrastim approximately 27 h after application.Methods: This prospective study examined patients with breast cancer who received chemotherapy with a high risk of FN, receiving OBI ("OBI") or other options (other G-CSF or none; "other"). The primary endpoint was FN incidence; secondary endpoints included chemotherapy delivery, adherence (G-CSF in all cycles), compliance (G-CSF day after chemotherapy), and FN incidence in patients receiving curative or palliative treatment.Results: A total of 1776 patients with breast cancer were enrolled (OBI, n = 1196; other, n = 580). Across all cycles, FN incidence was lower for OBI (4.4% [95% CI, 3.3-5.6%]) than other (7.4% [5.3-9.6%]). For curative treatment, the FN incidence across all cycles was lower for OBI (4.6% [3.4-5.8%]) than for other (7.1% [5.0-9.3%]). For palliative treatment (OBI, n = 33; other, n = 20), 3 patients (15%) in the other and none in the OBI group had FN. After adjusting for baseline covariates, FN incidence remained lower for OBI (4.6% [3.5-6.1%]) versus other (7.8% [5.7-10.5%]). Adherence was higher for OBI (93.8%) than for other G-CSF (69.8%), as was compliance (90.5 and 53.2%, respectively). Chemotherapy dose delays/reductions were similar for OBI (4.7%/32.3%, respectively) and other (4.7%/30.0%) groups.Conclusion: Pegfilgrastim OBI was associated with a lower FN incidence in patients with breast cancer compared to other options for FN prophylaxis.Trial Registration: www.Clinicaltrials: gov , NCT02178475, registered 30 June, 2014. [ABSTRACT FROM AUTHOR]

Purpose: To assess and describe patient-reported outcomes (PROs) in women with locally advanced/unresectable or metastatic breast cancer (aBC/mBC) with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 −) status receiving palbociclib combination therapy in a US real-world setting. Methods: A prospective, noninterventional, multicenter longitudinal study was conducted in US patients initiating treatment with palbociclib combination therapy for HR + /HER2 − aBC/mBC. PRO data (SF-12; CES-D-10; mood; pain; fatigue; interference of aBC/mBC or its treatment on family life, social life, physical activity, energy, and productivity; overall health rating; and quality of life [QOL]) were collected via a custom-developed mobile application at daily, weekly, and cycle-based intervals. Patient medical information (demographics, clinical characteristics, treatment information, and adverse events) was collected from medical records at baseline and at the end of the 6-month follow-up period. Results: Patients' general health status (SF-12) remained consistent throughout treatment and was generally consistent with published norms for individuals diagnosed with cancer. The presence of depression (CES-D-10) was low and did not change substantially over time. Mean pain and fatigue scores using an 11-point numeric rating scale were low and remained stable. Patients, on average, reported neutral or positive moods. Patient-reported QOL and overall health was primarily "Good," "Very good," or "Excellent." Findings were consistent regardless of patient experience with neutropenia. Conclusions: Patients treated with palbociclib, on average, reported consistently low levels of pain and fatigue as well as good QOL and overall health that remained stable throughout the first 6 months of treatment regardless of episodes of neutropenia. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic breast cancer is regarded as an incurable entity. In heavily pretreated patients with increasingly limited options for palliative management, ensuring proper quality of life continues is to be an elusive issue. With this in mind, the authors evaluated the efficacy and safety of the Vinorelbine/Capecitabine doublet (VINOCAP). Patients and methods: The investigators retrospectively analyzed a cohort of 67 women with HER2 negative MBC treated at a large breast cancer practice and a local cancer center with Vinorelbine 22.5 mg/m2 IV on days 1 and 8 combined with Capecitabine 1 g PO BID for 14 consecutive days of 21 day cycles. Patients had been treated with an average of 4 prior lines of chemotherapy. Patient characteristics and outcomes were evaluated. Results: A total of 67 patients received VINOCAP, and an additional 2 underwent repeat exposure yielding a cohort of 69. Clinical benefit rate, defined as complete response (CR), partial response (PR) or stable disease ≥ 6 months (SD), was 55.07%. Complete response was seen in 4.34%, PR in 18.8% and SD ≥ 6 months in 31.9%. Median progression-free survival was 6.2 months and overall survival 35.47 months after VINOCAP exposure. The most common grade 3–4 toxicity was neutropenia in 10% of cases. Dose had to be reduced in 18% of cases due to toxicity of any type. The regimen was well tolerated, and serious side effects were uncommon. Conclusion: Vinorelbine/Capecitabine appears to be an active and well-tolerated regimen in women with MBC. In particular, encouraging was the efficacy of VINOCAP as fourth or greater line of chemotherapy. [ABSTRACT FROM AUTHOR]

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

Purpose: Management of breast cancer is a rapidly evolving field, and, although evidence-based guidelines are available for clinicians to provide direction on critical issues in patient care, clinicians often left to address these issues in the context of community practice situations with their patients. These include the patient’s comorbid conditions, actual versus perceived benefit of treatments, patient’s compliance as well as financial/reimbursement issues, and long-term tolerability of therapy.Methods: A meeting of global oncology experts was convened in January 2017 with the belief that there is a gap in clinical practice guidance on several fundamental issues in breast cancer care, particularly in the community setting, where oncologists may encounter multiple tumor types. The goal was to discuss some of the most important questions in this area and provide some guidance for practicing oncologists.Results: Topics addressed included risk of contralateral breast cancer recurrence in patients with estrogen receptor-positive early breast cancer who have undergone 5 years of adjuvant endocrine therapy, adverse events associated with endocrine therapy and their management, emergent data on adjuvant bisphosphonate therapy and its apparent benefit in reducing breast cancer recurrence, recent findings of extended adjuvant endocrine therapy trials, and the use of currently available genomic biomarker tests as a means of further informing treatment decisions.Conclusions: A summary of the discussion on these topics and several ‘expert opinion statements’ are provided herein in an effort to convey the collective insights of the panel as it relates to current standard practice. [ABSTRACT FROM AUTHOR]

Approximately 6 % of patients with breast cancer are diagnosed with de-novo distant metastases. We set out to look at two cohorts of patients seen at breast cancer-specific practices, compare the results to other reports and larger databases, and see how advances in treatment have impacted overall survival (OS). The records from a large breast cancer oncology private practice and a second data set from the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC) tumor database were, retrospectively, reviewed to identify patients with de-novo metastases. We included those patients identified to have metastatic disease within 3 months of diagnosis of a breast primary cancer. Patients diagnosed between 1996 and 2006 were chosen for our study population. The OS for the private practice was 41.0 months (46.0 for ER positive and 26.0 for ER negative) and 36.0 months for UM/SCCC (52 months for ER positive and 36 months for ER negative). ER negativity and CNS- or visceral-dominant disease were associated with a significantly worse prognosis within the private practice. Dominant site was associated with a significantly worse prognosis within the UM/SCCC database but with a trend also for ER negativity. Age and ethnicity did not contribute significantly to the survival of patients within either cohort. The median survival in both cohorts and most other reported series was larger than that seen in the surveillance, epidemiology, and end results program and the National Cancer Database. The median OS among patients with de-novo metastatic breast cancer treated within two breast-specific oncology practices was over 3 years, which appears better than larger, more inclusive databases and publications from earlier decades. [ABSTRACT FROM AUTHOR]

To determine if a low fixed dosing strategy of capecitabine would produce comparable clinical activity with less adverse toxicities compared to published data with higher doses in the setting of metastatic breast cancer (mBC). We retrospectively analyzed patients treated with a low fixed dose of capecitabine (CAPE-L) at 1,000 mg twice daily for 14 days every 21 days. Outcomes included clinical benefit rate (CBR), overall response rates (ORR), time to progression (TTP), and overall survival (OS). A historical comparison group of mBC patients treated on 12 prior trials at the package-insert dose of capecitabine ( n = 1,949) was utilized. Eighty-six patients were analyzed in our cohort. Positive hormone receptor status (79.1 vs. 50.6 %), and capecitabine as first-line chemotherapy (44.2 vs. 16.5 %) were more frequent in our cohort relative to the historical comparison. The median starting dose in our cohort was 633.5 mg/m. The CBR was similar between the CAPE-L and the standard dose cohorts (55.8 vs. 49.5 %), as was ORR (24.3 vs. 24 %), and median TTP (7 mo, 95 % CI 5.5-8.5 vs. 5.1 mo, 95 % CI 4.5-5.7). Median OS was longer in our cohort (24 mo, 95 % CI 16.8-31.2) than the historic standard dose cohort (12.1 mo, 95 % CI 9.6-14.4), a difference that was likely explained by the higher proportion of patients in the CAPE-L cohort who received capecitabine as first-line chemotherapy and who had hormone receptor positive disease. As expected, adverse events were less frequent with CAPE-L. We found that CAPE-L, which translates into a dose of 600-650 mg/m, appeared to have good clinical efficacy and acceptable toxicity. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon's two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33-72) enrolled with a median of six prior chemotherapeutic regimens (range 2-20). On study, patients received a median of three treatment cycles (range 1-12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1-8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m² weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing. [ABSTRACT FROM AUTHOR]