Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.

BACKGROUND: Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. DESIGN AND METHODS: In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. RESULTS AND CONCLUSIONS: We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.

Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period. Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States). Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0-23.8) for all, 7.2 years (0.0-23.2), for M0, 2.6 years (0.0-12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Genetics of breast cancer: a topic in evolution.

A hereditary predisposition to breast cancer significantly influences screening and follow-up recommendations for high-risk women. However, in patients with a suggestive personal and/or family history, a specific predisposing gene is identified in <30% of cases. Up to 25% of hereditary cases are due to a mutation in one of the few identified rare, but highly penetrant genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11), which confer up to an 80% lifetime risk of breast cancer. An additional 2%-3% of cases are due to a mutation in a rare, moderate-penetrance gene (e.g. CHEK2, BRIP1, ATM, and PALB2), each associated with a twofold increase in risk. Prediction models suggest that there are unlikely to be additional yet to be identified high-penetrance genes. Investigation of common, low-penetrance alleles contributing to risk in a polygenic fashion has yielded a small number of suggestive single-nucleotide polymorphisms (SNPs), but the contributive risk of an individual SNP is quite small. Mutation testing is currently recommended for individual genes in the appropriate clinical setting where there is a high index of suspicion for a specific mutated gene or syndrome. Next-generation sequencing offers a new venue for risk assessment. At the present time, there are clear clinical guidelines for individuals with a mutation in a high-penetrance gene. Otherwise, standard models are used to predict an individual's lifetime risk by clinical and family history rather than genomic information.

Endogenous DNA damage and testicular germ cell tumors.

Testicular germ cell tumors are comprised of two histologic groups, seminomas and non-seminomas. We postulated that the possible divergent pathogeneses of these histologies may be partially explained by variable levels of net endogenous DNA damage. To test our hypothesis, we conducted a case-case analysis of 51 seminoma and 61 non-seminoma patients using data and specimens from the Familial Testicular Cancer study and the U.S. Radiologic Technologists cohort. A lymphoblastoid cell line was cultured for each patient and the alkaline comet assay was used to determine four parameters: tail DNA, tail length, comet distributed moment (CDM) and Olive tail moment (OTM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. Values for tail length, tail DNA, CDM and OTM were modelled as categorical variables using the 50th and 75th percentiles of the seminoma group. Tail DNA was significantly associated with non-seminoma compared with seminoma (OR(50th percentile) = 3.31, 95% CI: 1.00, 10.98; OR(75th percentile) = 3.71, 95% CI: 1.04, 13.20; p for trend = 0.039). OTM exhibited similar, albeit statistically non-significant, risk estimates (OR(50th percentile) = 2.27, 95% CI: 0.75, 6.87; OR(75th percentile) = 2.40, 95% CI: 0.75, 7.71; p for trend = 0.12) whereas tail length and CDM showed no association. In conclusion, the results for tail DNA and OTM indicate that net endogenous levels are higher in patients who develop non-seminoma compared with seminoma. This may partly explain the more aggressive biology and younger age-of-onset of this histologic subgroup compared with the relatively less aggressive, later-onset seminoma.

Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives.

Testicular germ cell tumours (TGCT) cluster in families, but responsible genes remain unidentified. The association between testicular microlithiasis (TM) and testicular carcinoma in situ (CIS) suggests that TM may be a TC risk factor. We report testicular ultrasound findings in men with familial TGCT (FTGCT) and their unaffected relatives. A total of 81 men (48 affected and 33 unaffected) from 31 families with > or =2 TC cases underwent testicular ultrasound. Testicular microlithiasis was defined as either 'classic' (> or =5 microliths) or 'limited' (<5 microliths). Statistical analyses used Fisher's exact test and permutation testing. Testicular microlithiasis was more frequent in the contralateral testicles of men with a history of TGCT (affected men) than in unaffected men (48 vs 24%, P=0.04). The association appeared stronger for classic TM (21 vs 9%) than for limited TM (27 vs 15%). Testicular microlithiases were bilateral in six out of seven (87%) unaffected men. Among affected men, TM was not associated with histology, age at diagnosis or cancer treatment. Of the 31 families, 10 accounted for a majority (61%) of the TM cases identified (P=0.11). Testicular microlithiasis was more prevalent among FTGCT family members than described previously in the general population, and was more common among FTGCT cases vs unaffected blood relatives. Testicular microlithiasis appeared to cluster in certain families. These findings suggest both a familial predisposition to TM and an association between TM and FTGCT. If proven, this could be clinically important to men in FTGCT families, and may be useful in identifying specific genes involved in FTGCT.