Quantification of HER2 heterogeneity in breast cancer–implications for identification of sub-dominant clones for personalised treatment

586 Background: HER2 heterogeneity (GH) has been described in breast cancer that has conventionally been labeled as HER2 negative (FISH score <2.2). We aimed to ascertain the prevalence of GH in HER2 negative breast cancers and to investigate for any impact on survival. Methods: We reviewed HER2 FISH (Vysis) data for 158 primary breast cancer specimens from 2006-2010 which were 0 – 2+ on immunohistochemistry. HER2:CEP17 ratios were calculated for each of the 60 cells scored and cases were classified as HER2 GH according to the ASCO/CAP guidelines (GH = 5-50% tumor cells with a ratio >2.2). Results: 67% (106/158), 7% (11/158) and 26% (41/158) were HER2 negative, equivocal (FISH ratio 1.8-2.2) and positive respectively. GH was found in 43% and 100% of Her2 negative and HER2 equivocal patients respectively. Of the 117 cases (with FISH score <2.2), HER 2 GH was associated with higher histologic grade (grade 3: 81.8%, 52.3% and 33.3% in HER2 equivocal, negative with GH and negative without GH (p = 0.007). There were no significant associations with ER status or the presence of lymphovascular invasion. The mean overall survival was 63 months (95% CI 43-87), 118 months (95% CI 96-141) and 148 months (95% CI 148-168) for HER 2 equivocal, negative with GH and negative without GH patients respectively (p=0.017). In a subset analysis of HER2 negative (with FISH score <2.2), non metastatic patients, with at least a 4 year follow up period (n=63), mean overall survival was 79 months (95% CI 60-98), 119 months (95% CI 96-143) and 159 months (95% CI 139-180) for HER2 equivocal, negative with GH and negative without GH patients (p=0.034). GH remained a significant factor in the multivariate analysis irrespective of grade, stage and ER status (p=0.046). Conclusions: HER2 GH occurs in 100% of HER2 equivocal and 43% of HER2 negative breast cancers and is associated with higher histologic grade and poorer overall survival, irrespective of grade, stage or hormonal status.

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Neoadjuvant Therapy for Breast Cancer as a Model for Translational Research

Breast Cancer Basic and Clinical Research ◽

10.1177/1178223419829072 ◽

2019 ◽

Vol 13 ◽

pp. 117822341982907 ◽

Cited By ~ 8

Author(s):

Cigdem Selli ◽

Andrew H Sims

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Tumour Response ◽

Breast Conserving Surgery ◽

Response To Treatment ◽

Surgical Removal ◽

Molecular Response ◽

Cancer Dormancy ◽

Personalised Treatment ◽

Surgical Setting

Neoadjuvant therapy, where patients receive systemic therapy before surgical removal of the tumour, can downstage tumours allowing breast-conserving surgery, rather than mastectomy. In addition to its impact on surgery, the neoadjuvant setting offers a valuable opportunity to monitor individual tumour response. The effectiveness of standard and/or potential new therapies can be tested in the neoadjuvant pre-surgical setting. It can potentially help to identify markers differentiating patients that will potentially benefit from continuing with the same or a different adjuvant treatment enabling personalised treatment. Characterising the molecular response to treatment over time can more accurately identify the significant differences between baseline samples that would not be identified without post-treatment samples. In this review, we discuss the potential and challenges of using the neoadjuvant setting in translational breast cancer research, considering the implications for improving our understanding of response to treatment, predicting therapy benefit, modelling breast cancer dormancy, and the development of drug resistance.

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