Associations of preoperative breast magnetic resonance imaging with subsequent mastectomy and breast cancer mortality.

PURPOSE: To examine associations between pre-operative magnetic resonance imaging (MRI) use and clinical outcomes among women undergoing breast-conserving surgery (BCS) with or without radiotherapy for early-stage breast cancer. METHODS: We identified women from the Surveillance, Epidemiology, and End Results-Medicare dataset aged 67-94 diagnosed during 2004-2010 with stage I/II breast cancer who received BCS. We compared subsequent mastectomy and breast cancer mortality with versus without pre-operative MRI, using Cox regression and competing risks models. We further stratified by receipt of radiotherapy for subgroup analyses. RESULTS: Our sample consisted of 24,379 beneficiaries, 4691 (19.2%) of whom received pre-operative MRI. Adjusted rates of subsequent mastectomy and breast cancer mortality were not significantly different with and without MRI: 3.2 versus 4.1 per 1000 person-years [adjusted hazard ratio (AHR) 0.92; 95% confidence interval (CI) 0.70-1.19] and 5.3 versus 8.7 per 1000 person-years (AHR 0.89; 95% CI 0.73-1.08), respectively. In subgroup analyses, women receiving BCS plus radiotherapy had similar rates of subsequent mastectomy (AHR 1.17; 95% CI 0.84-1.61) and breast cancer mortality (AHR 1.00; 95% CI 0.80-1.24) with versus without MRI. However, among women receiving BCS alone, MRI use was associated with lower risks of subsequent mastectomy (AHR 0.60; 95% CI 0.37-0.98) and breast cancer mortality (AHR 0.57; 95% CI 0.36-0.92). CONCLUSIONS: Pre-operative MRI was associated with improved outcomes among older women with breast cancer receiving BCS alone, but not among those receiving BCS plus radiotherapy. Further research is needed to identify appropriate settings for which MRI may be helpful.

New Therapeutic Strategies for Triple-Negative Breast Cancer.

Relatively few clinically important therapeutic advances have occurred in the treatment of triple-negative breast cancer (TNBC) since the introduction of taxanes as adjuvant therapy over 20 years ago. However, this is rapidly changing due to a variety of conceptually important clinical trials and emerging new options such as immune checkpoint inhibitors and antibody-drug conjugates. Evidence also increasingly supports that platinum drugs and inhibitors of poly (ADP-ribose) polymerase, or PARP, are particularly effective in the treatment of germline BRCA-mutant cancers, including TNBC. An important development in early-stage TNBC was the recognition that extensive residual cancer after neoadjuvant chemotherapy identifies patients who remain at high risk for recurrence. This has led to the design of two ongoing adjuvant trials (one testing pembrolizumab, the other investigating platinum drugs and capecitabine) that offer a "second chance" to improve the survival of patients with residual cancer after neoadjuvant chemotherapy. Genomic analysis of TNBC has revealed large-scale transcriptional, mutational, and copy number heterogeneity, without any frequently recurrent mutations, other than TP53. Consistent with this molecular heterogeneity, most targeted agents, so far, have demonstrated low overall activity in unselected TNBC, but important "basket" trials are ongoing.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. METHODS: Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

A Phase II Study Evaluating Orteronel, an Inhibitor of Androgen Biosynthesis, in Patients With Androgen Receptor (AR)-Expressing Metastatic Breast Cancer (MBC).

BACKGROUND: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). METHODS: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. RESULTS: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). CONCLUSIONS: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.

Bidirectional Text Messaging to Monitor Endocrine Therapy Adherence and Patient-Reported Outcomes in Breast Cancer.

INTRODUCTION: Up to 40% of patients with breast cancer may not adhere to adjuvant endocrine therapy. Therapy-related adverse effects (AEs) are important contributors to nonadherence. We developed a bidirectional text-message application, BETA-Text, that simultaneously tracks adherence, records symptoms, and alerts the clinical team. PATIENTS AND METHODS: We piloted our intervention in 100 patients. The intervention consisted of text messages to which patients responded for 3 months: daily, evaluating adherence; weekly, evaluating medication-related AEs; and monthly, regarding barriers to adherence. Concerning responses prompted a telephone call from a clinic nurse. The primary objective was to assess patient acceptance of this intervention using self-reported surveys. To compare participants with the general population at our institution, we assessed 100 consecutively treated patients as historical controls using medical record review. RESULTS: We approached 141 consecutive patients, 100 (71%) of whom agreed to participate and 89 of whom completed the intervention. A majority of patients reported that the intervention was easy to use (98%) and helpful in taking their medication (96%). Four patients discontinued therapy before 3 months, and 93% of patients who continued therapy took ≥ 80% of their medication. The frequency of AEs reported by participants via text was higher than that reported in clinical trials: hot flashes (72%), arthralgias (53%), and vaginal symptoms (35%). Approximately 39% of patients reported one or more severe AE that prompted an alert to the provider team to call the patient. CONCLUSION: A daily bidirectional text-messaging system can monitor adherence and identify AEs and other barriers to adherence in real time without inconveniencing patients. AEs of endocrine therapy, as detected using this texting approach, are more prevalent than reported in clinical trials.