Interaction between Hormonal Receptor Status, Age and Survival in Patients with BRCA1/2 Germline Mutations: A Systematic Review and Meta-Regression.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are the most frequent known hereditary causes of familial breast cancer. Little is known about the interaction of age at diagnosis, estrogen receptor (ER) and progesterone receptor (PgR) expression and outcomes in patients with BRCA1 or BRCA2 mutations. METHODS: A PubMed search identified publications exploring the association between BRCA mutations and clinical outcome. Hazard ratios (HR) for overall survival were extracted from multivariable analyses. Hazard ratios were weighted and pooled using generic inverse-variance and random-effect modeling. Meta-regression weighted by total study sample size was conducted to explore the influence of age, ER and PgR expression on the association between BRCA mutations and overall survival. RESULTS: A total of 16 studies comprising 10,180 patients were included in the analyses. BRCA mutations were not associated with worse overall survival (HR 1.06, 95% CI 0.84-1.34, p = 0.61). A similar finding was observed when evaluating the influence of BRCA1 and BRCA2 mutations on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89-1.61, p = 0.24; BRCA2: HR 1.01, 95% CI 0.80-1.27, p = 0.95). Meta-regression identified an inverse association between ER expression and overall survival (ß = -0.75, p = 0.02) in BRCA1 mutation carriers but no association with age or PgR expression (ß = -0.45, p = 0.23 and ß = 0.02, p = 0.97, respectively). No association was found for BRCA2 mutation status and age, ER, or PgR expression. CONCLUSION: ER-expression appears to be an effect modifier in patients with BRCA1 mutations, but not among those with BRCA2 mutations.

Outcomes of Estrogen Receptor Negative and Progesterone Receptor Positive Breast Cancer.

PURPOSE: To describe the clinical features and outcomes of estrogen receptor negative (ER-) and progesterone receptor positive (PgR+) breast cancer. METHODS: We retrospectively reviewed a well-characterized database of sequential patients diagnosed with early stage invasive breast carcinoma. Outcomes of interest were time to relapse (TTR) and overall survival (OS). Multivariable Cox proportional hazards analysis was conducted to assess the association of ER-/PgR+ with TTR and OS in comparison to ER+ and to ER- and PgR negative (ER-/PgR-) tumors irrespective of HER2 status. ER and PgR expression was conservatively defined as 10% or greater staining of cancer cells. RESULTS: 815 patients were followed for a median of 40.5 months; 56 patients (7%) had ER-/PgR+, 624 (77%) had ER+ and 136 (17%) had ER-/PgR- phenotypes. Compared with ER+ tumors, ER-/PgR+ tumors were associated with younger age (50 versus 59 years, p=0.03), high grade (50% versus 24%, p<0.001) and more frequent HER2 overexpression/amplification (43% versus 14%, p<0.001). TTR for ER-/PgR+ was intermediate between ER+ and ER-/PgR- tumors, but was not significantly different from ER+ tumors. Recurrences in the ER-/PgR+ and ER-/PgR- groups occurred early in follow-up while in ER+ tumors recurrences continued to occur over the duration of follow-up. OS of ER-/PgR+ was similar to ER+ tumors and better than that of ER-/PgR- tumors. CONCLUSIONS: The ER-/PgR+ phenotype is associated with higher grade with HER2 overexpression/amplification and occurs more commonly in younger women. Risk of relapse and death more closely resembles ER+ than ER-/PgR- tumors suggesting this phenotype represents a group of more aggressive hormone receptor positive tumors.

Association between androgen receptor expression, Ki-67 and the 21-gene recurrence score in non-metastatic, lymph node-negative, estrogen receptor-positive and HER2-negative breast cancer.

BACKGROUND: The mechanisms underlying the favourable prognosis of androgen receptor (AR) expression in breast cancer are unknown. METHODS: The associations between the 21-gene recurrence score (RS), AR, grade, mitotic score, Ki-67 and estrogen receptor (ER) and progesterone receptor (PgR) expression were explored in sequential women with lymph node-negative, ER-positive and HER2-negative breast cancer. Statistical significance of this exploratory study was defined as p<0.10. RESULTS: Analysis comprised 70 women. Most tumours had high AR expression (97% had scores >3). Median RS was 15 (range 1-53). AR expression showed a minimally significant positive correlation with ER (R=0.37), but no correlation with Ki-67 (R=-0.18). In univariable analysis, AR (p=0.01), ER (p<0.001) and PgR (p<0.001) had significant negative associations with RS. Ki-67 (p=0.16), grade (p=0.40) and mitotic score (p=0.23) showed no association with RS. Multivariable analysis showed similar associations. CONCLUSIONS: AR is associated with lower RS, but not with Ki-67.

Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases.

While de-escalation of bisphosphonates from 4 to 12-weekly dosing has been shown to be clinically non-inferior to standard dosing, there is evidence the de-escalation is associated with increased bone turnover biomarkers. Here we evaluated the effect of de-escalated dosing on a panel of biomarkers and determined their association with incidence of skeletal related events (SREs) in breast cancer patients with 'low risk' bone metastases. As part of a pilot randomized trial, women with baseline C-telopeptide levels <600 ng/L after >3 months of 3-4 weekly pamidronate were randomized to continue pamidronate every 4 weeks or de-escalation to 12-weekly treatment. Serum was analysed for bone biomarkers (C-telopeptide, N-telopeptide, bone-specific alkaline phosphatase, transforming growth factor-ß, procollagen type 1 N-propeptide, activinA and bone sialoprotein) using ELISA. The associations between changes in biomarkers, pain scores and SREs were assessed by univariable logistic regression. Numerical increases in all biomarkers were observed between baseline and 12 weeks but were of higher magnitude in the de-escalated arm. Pain scores in the de-escalated treatment arm showed a greater magnitude of pain reduction from baseline to 12 weeks. Neither baseline levels nor changes in biomarkers from baseline to 12 weeks on treatment were associated with on study SREs. Baseline pain as measured by the FACT-BP was associated with increased risk of SRE. In conclusion, biomarkers of bone activity do not appear to predict for SREs in 'low risk' cohorts. However, baseline bone pain appears to be associated with SRE occurrence, a finding which warrants evaluation in larger cohorts.

The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs.

PURPOSE: Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration. PATIENTS AND METHODS: We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed. RESULTS: Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS. CONCLUSION: New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.