Katherine A. Hoadley, PhD, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA, presented the mutational analysis of the Paclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With Stage II or Stage III Breast Cancer That Can Be Removed by Surgery trial [CALGB 40601; NCT00770809].

CALGB 40601 was a neoadjuvant trial in which patients with human epidermal growth factor receptor 2 (HER2)–positive clinical stage II or III breast cancer (BC) had a pretreatment biopsy research tissue sample taken at random assignment to weekly paclitaxel (T) plus trastuzumab (H) plus lapatinib (L) for 16 weeks (n = 118); or T plus H for 16 weeks (n = 120); or T plus L for 16 weeks (n = 67) [Carey LA et al. ASCO 2013 (abstr 500)]. A second research tissue sample was obtained at surgery following the neoadjuvant treatment. There was no statistically significant difference between treatment groups in pathologic complete remission (pCR) rates. RNA from pretreatment samples were correlated with pCR by intrinsic subtype in all arms (n = 265). The pCR rate for the HER2-enriched subtype (n = 82) has twice the pCR rate (70%) as luminal A (n = 80; 34%) or luminal B (n = 80; 36%) [Carey LA et al. J Clin Oncol. 2014].

The mutational analysis evaluated 181 HER-positive pretreatment tumors and correlated 9 genes (TP53, PIK3CA, GATA3, AKT1, ERBB2, MAP3K1, MAP2K4, TRPS1, and MALAT1) with pCR rates. To increase the power to detect somatic mutations, UNCeqR, a program that integrates RNA and DNA sequencing, was used [Wilkerson MD et al. Nucleic Acids Res. 2014].

A median of 62 total mutations (interquartile range 32-118) was found. The number of mutations varied significantly by intrinsic subtype (P < .001) and by TP53 mutation status (P < .001). The HER2-enriched and luminal B subtypes had higher numbers of mutations. TP53 mutations also correlated with higher numbers of mutations.

TP53 had a mutation frequency of 56%, PIK3CA had a mutation frequency of 20%, and the rest of the 9 genes had a mutation frequency of < 10%. TP53 mutations were significantly associated with pCR. In the overall population, the odds ratio was 3.67 (P < .001) for pCR vs wild type for those with mutated TP53; the odds ratio was 5.23 (P = .007) for pCR with luminal A mutations vs wild type. No other genes examined were correlated with pCR.

There were 8 HER2/ERBB2 mutations in 7 patients; 2 of the 8 HER2 mutations were previously shown to be activating mutations [Bose R et al. Cancer Discov. 2013]. A patient in the THL arm with HER2-enriched with V777L, preclinically predicted sensitive to L, had pCR. A patient in the TL arm with luminal A with L755S, preclinically predicted resistant to L, did not have pCR.

TP53 was the most frequently mutated gene in this cohort and was associated with increased pCR and a higher somatic mutation rate. Activating HER2 mutations were uncommon but behaved as predicted from preclinical studies. Future studies to use genomic signatures, somatic mutations, and clinical variables for pCR predictions are underway.