Association of Somatic Driver Alterations With Prognosis in Postmenopausal, Hormone Receptor-Positive, HER2-Negative Early Breast Cancer: A Secondary Analysis of the BIG 1-98 Randomized Clinical Trial

Abstract

Importance: A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown.

Objective: To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole.

Design, setting, and participants: The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2- BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016.

Main outcomes and measures: The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors.

Results: Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002).

Conclusions and relevance: In ER+/HER2- postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting.

Trial registration: ClinicalTrials.gov Identifier: NCT00004205.

Conflict of interest statement

Conflict of Interest Disclosures: Mr Demanse and Drs JeBailey, Dolan, and Hackl are employees of Novartis. Dr Colleoni has received honoraria from Novartis and acted as unpaid consultant to Pierre Fabre, Pfizer, OBI Pharma, Puma Biotechnology, Celldex, and AstraZeneca. Dr Regan has received research funding and/or provision of drug supply for clinical trials from Novartis, Pfizer, Ipsen, Merck, Ferring, Celgene, AstraZeneca, Pierre Fabre, and Roche; research funding from Novartis, Veridex, OncoGenex, Bayer, and Bristol-Myers Squibb; and serves in an unpaid consulting or advisory role for Ipsen, Merck, and Bristol-Myers Squibb. Prof Loi receives research funding to her institution from Novartis, BMS, Merck, Roche-Genentech, Puma Biotechnology, and Pfizer, and serves as an uncompensated consultant for Seattle Genetics, Pfizer, Novartis, BMS, Merck, and Roche-Genetech. No other conflicts were reported.

Figures

Figure 1.. Flow Diagram of Patient Selection for the Analysis Population

ER indicates estrogen receptor.

Figure 2.. The Landscape of Somatic Driver Alterations in the Breast International Group 1-98 Trial

Only somatic driver alterations with a weighted frequency of 4% or greater in the whole cohort are displayed. All percentages shown are weighted frequencies with the exception of estrogen receptor (ER) and progesterone receptor (PR) expression. Luminal-like status was determined using the published St Gallen 2013 consensus. Thirteen patients were luminal-like status unknown because of missing data. Numbers in parentheses indicate absolute numbers of patients per cohort and subtype. Indels indicates insertions and deletions; LN, lymph node.

Figure 3.. Prognostic Analyses for Distant Recurrence

Weighted univariate and multivariable Cox proportional hazards regression analyses are shown for distant recurrence-free interval. The hazard ratio (HR) compares the mutated or amplified status vs the wild-type or nonamplified status of the gene (or amplicon), respectively. Number of alterations was evaluated as a continuous variable per additional driver alteration. Number of events indicates the observed number of distant recurrences in the analysis cohort. The univariate Cox proportional hazards regression model was adjusted for treatment arm, and the multivariable model was adjusted for treatment arm, age, tumor size, nodal status, and grade as described in the Methods section. Focal gene amplifications on chromosomes 20q13, 11q13, and 8p11 are described in the Results section.

Figure 4.. Treatment Interactions

A and B, Weighted cumulative incidence curves demonstrating the prognostic effect of letrozole or tamoxifen monotherapy on the risk of distant recurrence by PIK3CA mutation status. Number of events indicates the observed number of distant recurrences per subgroup. The 5-year estimates for distant recurrence and 95% CIs were calculated with the use of sampling weights. C, Hazard ratio (HR) for letrozole monotherapy vs tamoxifen monotherapy according to PIK3CA mutation status. These data were derived with a weighted univariate Cox proportional hazards regression model. The interaction P value represents the interaction between PIK3CA mutation status and treatment benefit. The observed number of patients (number of events) was 114 (24) for the PIK3CA mutation-positive group and 184 (47) for PIK3CA mutation-negative group.