HER2 status and breast cancer therapy: recent advances

The phenotype imparted by expression of the HER2 gene in breast cancer and progress made in modifying the disease's natural history through pharmacologically modulating its function has served as a paradigm for rationally targeted therapy and personalized medicine. About 20-25% of breast cancer cases are associated with HER2 gene amplification and overexpression, creating a distinct subtype of breast cancer that is associated with more aggressive behaviour, higher likelihood of overall and brain metastases, and differential responsiveness to certain hormonal and chemotherapeutic agents. Anti-HER2 monoclonal antibodies have led to significant improvements in survival for both advanced and early stage HER2+ breast cancer, while newer agents, including other antibodies and HER2 receptor tyrosine kinase inhibitors and signal transduction modulators, are also demonstrating clinical activity and represent further opportunities to improve curability and quality of life

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea.

PurposeDiarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea.MethodsThis paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management.ResultsIn the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed-and continue to be refined-to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea.ConclusionsContinued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer.

Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed ≤6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index ≥30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade ≥3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3-32.1; white: 37.3, 95 % CI 34.6-41.1; PFS: black: 7.0, 95 % CI 5.7-8.2; white: 10.2, 95 % CI 9.3-11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00-1.65); adjusted PFS HR was 1.29 (95 % CI 1.05-1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences

HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer.

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.Methods/designHERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.DiscussionThe HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.Trial registrationClinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014

Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study.

Limited data exist regarding treatment patterns and outcomes in elderly patients with HER2-positive metastatic breast cancer (MBC). registHER is an observational study of patients (N = 1,001) with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up 27 months). Outcomes were analyzed by age at MBC diagnosis: younger (<65 years), older (65-74 years), elderly (≥75 years). For progression-free survival (PFS) and overall survival (OS) analyses of first-line trastuzumab versus nontrastuzumab, older and elderly patients were combined. Cox regression analyses were adjusted for baseline characteristics and treatments. Estrogen receptor/progesterone receptor status was similar across age groups. Underlying cardiovascular disease was most common in elderly patients. In patients receiving trastuzumab-based first-line treatment, elderly patients were less likely to receive chemotherapy. In trastuzumab-treated patients, incidence of left ventricular dysfunction (LVD) and congestive heart failure (CHF) (grades ≥ 3) were highest in elderly patients (LVD: elderly 4.8 %, younger 2.8 %, older 1.5 %; CHF: elderly 3.2 %, younger 1.9 %, older 1.5 %). Unadjusted median PFS (months) was significantly higher in patients treated with first-line trastuzumab than those who were not (<65 years: 11.0 vs. 3.4, respectively; ≥65 years: 11.7 vs. 4.8, respectively). In patients <65 years, unadjusted median OS (months) was significantly higher in trastuzumab-treated patients; in patients ≥65 years, median OS was similar (<65 years: 40.4 vs. 25.9; ≥65 years: 31.2 vs. 28.5). In multivariate analyses, first-line trastuzumab use was associated with significant improvement in PFS across age. For OS, significant improvement was observed for patients <65 years and nonsignificant improvement for patients ≥65 years. Elderly patients with HER2-positive MBC had higher rates of underlying cardiovascular disease than their younger counterparts and received less aggressive treatment, including less first-line trastuzumab. These real-world data suggest improved PFS across all age groups and similar trends for OS

Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials

Prognostic role of elevated mir-24-3p in breast cancer and its association with the metastatic process

MicroRNAs have been shown to play important roles in breast cancer progression and can serve as biomarkers. To assess the prognostic role of a panel of miRNAs in breast cancer, we collected plasma prospectively at the time of initial diagnosis from 1,780 patients with stage I-III breast cancer prior to definitive treatment. We identified plasma from 115 patients who subsequently developed distant metastases and 115 patients without metastatic disease. Both groups were matched by: age at blood collection, year of blood collection, breast cancer subtype, and stage. The median follow up was 3.4 years (range, 1-9 years). We extracted RNA from plasma and analyzed the expression of 800 miRNAs using Nanostring technology. We then assessed the expression of miRNAs in primary and metastatic breast cancer samples from The Cancer Genome Atlas (TCGA). We found that, miR-24-3p was upregulated in patients with metastases, both in plasma and in breast cancer tissues. Patients whose primary tumors expressed high levels of miR-24-3p had a significantly lower survival rate compared to patients with low mir-24-3p levels in the TCGA cohort (n=1,024). RNA-Seq data of the samples with the highest miR-24-3p expression versus those with the lowest miR-24-3p in the TCGA cohort identified a specific gene expression signature for those tumors with high miR-24-3p. Possible target genes for miR-24-3p were predicted based on gene expression and binding site, and their effects on cancer pathways were evaluated. Cancer, breast cancer and proteoglycans were the top three pathways affected by miR-24-3p overexpression

Clinical practice guidelines on the evidenceâ based use of integrative therapies during and after breast cancer treatment

Answer questions and earn CME/CNEPatients with breast cancer commonly use complementary and integrative therapies as supportive care during cancer treatment and to manage treatmentâ related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integrative Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapyâ induced nausea and vomiting, lymphedema, chemotherapyâ induced peripheral neuropathy, pain, and sleep disturbance. Clinical practice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapyâ induced nausea and vomiting. Acetylâ Lâ carnitine is not recommended to prevent chemotherapyâ induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatmentâ related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mindâ body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evidence to be definitively recommended or avoided. CA Cancer J Clin 2017;67:194â 232. © 2017 American Cancer Society.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136746/1/caac21397_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136746/2/caac21397.pd

Circulating Tumor Cell Transcriptomics as Biopsy Surrogates in Metastatic Breast Cancer

BACKGROUND Metastatic breast cancer (MBC) and the circulating tumor cells (CTCs) leading to macrometastases are inherently different than primary breast cancer. We evaluated whether whole transcriptome RNA-Seq of CTCs isolated via an epitope-independent approach may serve as a surrogate for biopsies of macrometastases. METHODS We performed RNA-Seq on fresh metastatic tumor biopsies, CTCs, and peripheral blood (PB) from 19 newly diagnosed MBC patients. CTCs were harvested using the ANGLE Parsortix microfluidics system to isolate cells based on size and deformability, independent of a priori knowledge of cell surface marker expression. RESULTS Gene expression separated CTCs, metastatic biopsies, and PB into distinct groups despite heterogeneity between patients and sample types. CTCs showed higher expression of immune oncology targets compared with corresponding metastases and PB. Predictive biomarker (n = 64) expression was highly concordant for CTCs and metastases. Repeat observation data post-treatment demonstrated changes in the activation of different biological pathways. Somatic single nucleotide variant analysis showed increasing mutational complexity over time. CONCLUSION We demonstrate that RNA-Seq of CTCs could serve as a surrogate biomarker for breast cancer macrometastasis and yield clinically relevant insights into disease biology and clinically actionable targets