Impact of androgen receptor expression in fluoxymesterone-treated estrogen receptor-positive metastatic breast cancer refractory to contemporary hormonal therapy.

PURPOSE: The purpose of this study is to evaluate survival outcome in patients with hormone receptor (HR)-positive (+) metastatic breast cancer (MBC) who received fluoxymesterone after disease progression while receiving contemporary hormonal therapy, as well as the association between estrogen receptor (ER)/androgen receptor (AR) status and survival outcome in these patients. METHODS: We retrospectively identified 103 patients treated with fluoxymesterone for HR + MBC from 2000 to 2014 and with at least one previous hormonal therapy in a metastatic setting. RESULTS: A median of 3 (range 1-10) hormonal therapies (aromatase inhibitors, tamoxifen, and/or fulvestrant) were received before fluoxymesterone; 33 patients discontinued fluoxymesterone before progression because of physician decision or adverse events including toxicity in 14 patients. Of the remaining 70 patients, 2 (3 %) had complete response, 7 (10 %) partial response, and 21 (30 %) stable disease for at least 6 months, yielding a clinical benefit rate of 43 %. The median PFS was 3.9 months (95 % CI 3.2-5.3 months). Multivariate analysis revealed no significant association between PFS and the type or number of prior systemic treatments. All 39 patients who had archived tumor slides available for AR staining had ER + carcinoma; 10 had ≥1 % but <10 %, 18 had ≥10 %, and 11 had no AR nuclear expression. AR positivity with various cutoffs (i.e. any AR + cells, ≥1 % AR + cells, or ≥10 % AR + cells) was not significantly associated with survival outcome. CONCLUSIONS: Fluoxymesterone can be considered for patients whose ER + MBC progresses on contemporary hormonal therapy, regardless of the level of AR expression.

Overall survival in older patients with cancer.

OBJECTIVES: A growing number of patients with cancer are older adults. We sought to identify the predictors for overall survival (OS) in older adults with solid tumour and haematological malignancies between January 2013 and December 2016. METHODS: Retrospective cohort study. A comprehensive geriatric assessment was performed, with a median follow-up of 12.8 months. ANALYSIS: univariate and multivariate Cox proportional hazards regression analysis. RESULTS: In this study, among the 455 patients with last follow-up date or date of death, 152 (33.4%) died during the follow-up. The median follow-up is 12.8 months (range 0.2-51.1 months) and the median OS is 20.5 months (range 0.3-44.5 months). Among all older patients with cancer, predictors of OS included male gender, cancer stage, malnutrition, history of smoking, heavy alcohol use, frailty, weight loss, major depression, low body weight and nursing home residence. Traditional performance scores (Eastern Cooperative Oncology Group (ECOG) and Karnofsky Performance Scale (KPS)) were predictors of OS. Independent predictors included age >85 years and haematological malignancies. Among solid tumours (n=311) in addition to the above predictors, comorbidity, gait speed and vitamin D deficiency were associated with OS. CONCLUSIONS: We identified specific geriatric factors associated with OS in older patients with cancer, and comparable in predictive ability to traditional performance scores such as KPS and ECOG. Prospective studies will be necessary to confirm our findings.

Long-term decision regret surrounding systemic therapy in older breast cancer survivors: A population-based survey study.

INTRODUCTION: Little is known regarding regret experienced by older breast cancer survivors surrounding the choice for adjuvant systemic therapy, which limits providers' ability to optimally engage in the shared decision-making process. To address this, we evaluated endocrine therapy and chemotherapy decisional regret in a population-based cohort of older breast cancer survivors. MATERIALS AND METHODS: Nationally comprehensive Medicare claims identified women age ≥67 living in the US with non-metastatic breast cancer diagnosed in 2009 and still alive in 2015. The Decision Regret Scale, a validated index that assesses regret regarding treatment decisions on a scale of 0 (no regret) to 100, was used to measure regret for endocrine therapy and chemotherapy approximately 6 years after diagnosis and was adjusted for sampling weight. Multivariable logistic regression adjusted for patient, demographic, and treatment characteristics identified predictors of endocrine therapy and chemotherapy decision regret. RESULTS: Of the 480 respondents, 299 patients (61.1%) reported receiving endocrine therapy and 133 (27%) chemotherapy. The overall weighted decision-regret score was 17.2 (95%CI 13.6-20.8) for endocrine therapy and 17.7 (95%CI 12.1-23.3) for chemotherapy. Risk factors for higher endocrine therapy regret included white race (referent non-white race; estimate 12.8, 95%CI 3.0-22.7; P = 0.01) and post-graduate educational attainment (referent college education; 11.6, 95%CI 1.9-21.3; P = 0.02). The only risk factor for chemotherapy regret, albeit marginal, was age ≥75 (referent age 67-74; 12.0, 95%CI -0.1-24.2; P = 0.05) CONCLUSION: Overall, decision regret levels regarding systemic therapy in older breast cancer survivors are reassuringly low. However, further studies are needed to explore drivers of regret in certain vulnerable subgroups of patients.

Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer.

PURPOSE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies. EXPERIMENTAL DESIGN: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment. RESULTS: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples. CONCLUSIONS: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib.

Androgen Receptor Function and Androgen Receptor-Targeted Therapies in Breast Cancer: A Review.

IMPORTANCE: The androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments. OBSERVATIONS: The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor-targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression. CONCLUSIONS AND RELEVANCE: Androgen receptor-targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

Targeted agent use in cancer patients at the end of life.

CONTEXT: The use of targeted therapy at the end of life has not been well characterized. OBJECTIVES: To determine the frequency and predictors of targeted therapy use in the last days of life. METHODS: All adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents. RESULTS: Eight hundred sixteen patients were included: average age 62 years (range 21-97), female 48% and white 61%. The median interval between the last treatment and death was 47 (interquartile range [IQR] 21-97) days for targeted agents and 57 (IQR 26-118) days for chemotherapeutic agents. Within the last 30 days of life, 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy. Regimens given in the last 30 days of life included a median of one (IQR 1-2) chemotherapeutic or targeted agent and 43 (5%) patients receiving targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib (n = 25), bevacizumab (n = 20), rituximab (n = 11), gemtuzumab (n = 8), and temsirolimus (n = 8). On multivariate analysis, younger age (odds ratio [OR] 0.98 per year, P = 0.01), hematologic malignancy (OR = 6.1, P < 0.001), and lung malignancy (OR = 2.6, P = 0.05) were associated with increased targeted agent use in the last 30 days of life. CONCLUSION: Targeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed.