A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients
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HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients.
We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR.
Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher’s exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER−)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group.
Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.
KeywordsGene expression profiling RB pathway HER2+ breast cancer Neoadjuvant chemotherapy Predictive marker
Area under the curve
Estrogen receptor positive
Estrogen receptor negative
Human epidermal growth factor receptor-2
- HER2 +
Human epidermal growth factor receptor-2 positive
Lymph node status
Pathological complete response
Phosphoinositide-3-kinase catalytic alpha polypeptide gene
Retinoblastoma tumor suppressor gene
RB1 loss-of-function gene signature
- T + A-based
Taxane–anthracycline-based chemotherapy or ixabepilone–anthracycline-based chemotherapy
- T + A-based + H
Taxane–anthracycline-based chemotherapy plus anti-HER2 drugs
We acknowledge the generous support provided by the Sandro Pitigliani Foundation (Prato, Italy), the Breast Cancer Research Foundation (BCRF) (New York, US), the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Milan, Italy), my first AIRC grant (MFAG) 18880 (to L.M.), AIRC Special Program Molecular Clinical Oncology “5 per mille,” and Italian Epigenomics Flagship Project (Epigen) (to S.B.). We are grateful to Patricia de Cremoux and the REMAGUS 02 trial investigators for providing the trial data.
Compliance with ethical standards
Conflicts of interest
A Di Leo is a consultant/advisory board member for AstraZeneca, Bayer, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, and Pierre Fabre. L. Malorni is a consultant for AstraZeneca and Pfizer. No potential conflicts of interest were disclosed by the other authors.
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