A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients
- 118 Downloads
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.
- 4.Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN et al (2016) Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase iii trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol 34:542–549CrossRefPubMedGoogle Scholar
- 5.Llombart-Cussac A, Cortés J, Paré L, Galván P, Bermejo B, Martínez N et al (2017) HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol 18:545–554CrossRefPubMedGoogle Scholar
- 10.Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C et al (2011) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32CrossRefPubMedGoogle Scholar
- 13.Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A et al (2009) Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 27:5529–5537CrossRefPubMedGoogle Scholar
- 14.Marcom PK, Isaacs C, Harris L, Wong ZW, Kommarreddy A, Novielli N et al (2007) The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat 102:43–49CrossRefPubMedGoogle Scholar
- 15.Huober J, Fasching PA, Barsoum M, Petruzelka L, Wallwiener D, Thomssen C et al (2012) Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer results of the eLEcTRA trial. Breast 21:27–33CrossRefPubMedGoogle Scholar
- 16.Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA et al (2013) Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726–1731CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Rimawi MF, Niravath PA, Wang T, Rexer B, Forero A, Wolff AC et al (2015) TBCRC023: a randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 versus 24 weeks in patients with HER2 overexpressing breast cancer. Cancer Res 75:S6CrossRefGoogle Scholar
- 22.Malorni L, Piazza S, Ciani Y, Guarducci C, Bonechi M, Biagioni C et al (2016) A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 7:68012–68022CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Guarneri V, Dieci MV, Frassoldati A, Maiorana A, Ficarra G, Bettelli S et al (2015) Prospective Biomarker analysis of the randomized CHER-LOB study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer. Oncologist 20:1001–1010CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Tabchy A, Valero V, Vidaurre T, Lluch A, Gomez H, Martin M et al (2010) Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer. Clin Cancer Res 16:5351–5361CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Valet F, de Cremoux P, Spyratos F, Servant N, Dujaric ME, Gentien D et al (2013) Challenging single- and multi-probesets gene expression signatures of pathological complete response to neoadjuvant chemotherapy in breast cancer: experience of the REMAGUS 02 phase II trial. Breast 22:1052–1059CrossRefPubMedGoogle Scholar
- 44.Finn R, Jiang Y, Rugo H, Moulder SL, Im S-A, Gelmon KA et al (2016) Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER+/HER2− advanced breast cancer (ABC). Ann Oncol 27:LBA15Google Scholar
- 46.Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ et al (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11:R77CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M et al (2018) Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. https://doi.org/10.1016/S1470-2045(18)30001-9 PubMedGoogle Scholar