Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. Significance: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection. See related commentary by Okines and Turner, p. 2369. This article is highlighted in the In This Issue feature, p. 2355

Our goal in this case report is to increase the awareness of surgeons and clinicians to rule out the possibility of mammary origin in circumstance of gastric cancer occurring in female, even in patients without a previous or concurrent history of breast carcinoma. Although not a particularly common event, it is, nevertheless, reported in the literature. The differentiation between primary gastric carcinoma and metastatic breast carcinoma is essential for planning the correct therapeutic approach, in order to avoid the patient unnecessary surgery.

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Background/Purpose Choice of therapy for breast cancer relies on human epidermal growth factor receptor-2 (HER2) and estrogen receptor (ER) status. Before randomization in the phase III adjuvant ALTTO trial for HER2-positive disease, HER2 and ER were centrally reviewed by Mayo Clinic (Rochester, MN and Scottsdale, AZ) for North America and by the European Institute of Oncology (IEO; Milan, Italy) for rest of world (except China). Discordance rates (local vs. central review) differed between Mayo and IEO. Among locally HER2-positive cases, 5.8% (Mayo) and 14.5% (IEO) were centrally HER2-negative. Among locally ER-positive cases, 16.2% (Mayo) and 4.2% (IEO) were centrally ER-negative. Among locally ER-negative cases, 3.4% (Mayo) and 21.4% (IEO) were centrally ER-positive. We, therefore, performed a ring study to identify features contributing to these differing discordance rates. Methods Mayo and IEO exchanged slides for 25 HER2 and 35 ER locally/centrally discordant cases. Both laboratories performed IHC and FISH for HER2 using the HercepTest® and PathVysion HER2 DNA probe kit/HER2/centromere 17 probe mixture. IHC for ER was tested centrally using the monoclonal ER 1D5 antibody (Mayo) or the DAKO cocktail of ER 1D5 and 2.123 antibodies (IEO). Results Mayo and IEO confirmed the central HER2-negative result in 100% of 25 cases. Mayo and IEO confirmed the central ER result in 29 (85%) of 34 evaluable cases. The five Mayo negative/IEO positive cases were ER-positive when retested at Mayo using the DAKO ER cocktail. Conclusions In this ring study, ALTTO ineligibility did not change when HER2 testing was performed by either IEO or Mayo central laboratories. However, a dual antibody ER assay had fewer false negative test results than an assay with a single antibody, there was more discordance between the two ER reagents than has been previously reported, and using even slightly different assay methods yielded different results, even between experienced central laboratories.