Abstract 4549: SNP array-based molecular analysis predicts response to neoadjuvant chemotherapy in triple negative and HER2-positive breast cancers
Authors: Takada Mamoru , Kaneko Yasihiko , Haruta Masayuki 
Published: August 2012

Patients with breast cancer (BC) who achieved pathological complete response (pCR) after neoadjuvant chemotherapy are expected to enjoy a long-term remission. However, the pCR rates ranged between 8% and 80% among the four types of BCs classified by immunohistochemistry, and it is important to predict the response to the chemotherapy to avoid unnecessary burden. We examined SNP array patterns in 144 untreated BC specimens; Luminal A (LA) 77 tumors, Luminal B (LB) 29, HER2 18, and triple-negative (TN) 20. The efficacy of the chemotherapy was pathologically assessed in 109 BCs after surgical resection. Anthracycline, cyclophosphamide, and taxane were given for LA and TN type patients and the 3 drugs plus trastuzumab and 5FU for LB and HER2 type patients. pCR was attained in 8%, 36%, 80%, and 27% of LA, LB, HER2, and TN type patients, respectively. Total numbers of genomic alteration (TGA) and uniparental disomy (UPD) per tumor were found in 15.2 and 2.3, 19.4 and 2.9, 20.2 and 3.3, and 30.5 and 7.6 in LA, LB, HER2, and TN type tumors, respectively. The frequency of TGA and UPD was higher in TNBCs than in non-TNBCs (P&lt;0.01). Promoter methylation of BRCA1 examined with MethyLight was found in 45% of TNBCs and 7% of non-TNBCs (P&lt;0.01). The Spearman correlation coefficient analysis showed that the methylation levels of the BRCA1 promoter correlated with the numbers of TGA and UPD in 134 BCs examined (0.325, P&lt;0.01 and 0.362, P&lt;0.01). Among TNBCs, pCR was more frequent in patients with the methylated tumor than in those with the unmethylated tumor (P=0.04). In contrast, no such association was found in LA or LB type patients. These findings suggest that a subgroup of TNBCs characterized by BRCA1 methylation and frequent genomic changes are likely to be induced into pCR, and that activation of the hormone receptor (HR) signaling pathway may confer the chemotherapy-resistance on HR-positive tumors with such molecular changes. Among 38 patients with HER2-positive BCs, 30 had HER2 amplification and 8 had a single copy of HER2. pCR was achieved in 63% of the 30 amplified tumors and only 13% of the 8 non-amplified tumors (P=0.01). The single copy number of HER2 was more frequent in LB type tumors than in HER2 type tumors (P=0.01). A HER2 splicing variant (HER2 del16) was reported to be a poor prognostic factor, and we quantified the levels of normal and del16 HER2 transcripts to identify whether the amount of del16 HER2 is associated with a single copy of HER2 or attainability of pCR. The amount of del16 HER2 was not associated with the HER2 copy number or the percentage of pCR. Loss or UPD of PTEN was found in 6 of 38 BCs. pCR was achieved in 9 of 18 tumors with normal PTEN, but in none of 6 tumors with abnormal PTEN. Because only 1 of 11 tumors with the single copy of HER2 and/or abnormal PTEN achieved pCR after receiving trastuzumab containing regimens, tyrosine kinase inhibitors should be given to the patients with such genetic changes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4549. doi:1538-7445.AM2012-4549