Elsevier

European Journal of Cancer

Volume 48, Issue 18, December 2012, Pages 3342-3354
European Journal of Cancer

Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy☆

https://doi.org/10.1016/j.ejca.2012.05.023Get rights and content

Abstract

Background

Pathologic complete response (pCR) is a surrogate end-point for prognosis in neoadjuvant chemotherapy (NAC) for breast cancer. We aimed to report summary estimates of the proportion of subjects achieving pCR (pCR%) by tumour subtype, and to determine whether subtype was independently associated with pCR, in a study-level meta-analysis.

Methods

We systematically identified NAC studies reporting pCR data according to tumour subtype, using predefined eligibility criteria. Descriptive, qualitative and quantitative data were extracted. Random effects logistic meta-regression examined whether pCR% was associated with subtype, defined using three categories for model 1 [hormone receptor positive (HR+/HER2–), HER2 positive (HER2+), triple negative (ER–/PR–/HER2–)] and 4 categories for model 2 [HER2+ further classified as HER2+/HR+ and HER2+/HR–]. Subtype-specific odds ratios (OR) were calculated and were adjusted for covariates associated with pCR in our data.

Results

In model 1, based on 11,695 subjects from 30 eligible studies, overall pooled pCR% was 18.9% (16.6–21.5%), and in model 2 (20 studies, 8095 subjects) pooled pCR% was 18.5% (16.2-21.1%); tumour subtype was associated with pCR% (P < 0.0001) in both models. Subtype-specific pCR% (model 2) was: 8.3% (6.7–10.2%) in HR+/HER2– [OR 1/referent], 18.7% (15.0–23.1%) in HER2+/HR+ [OR 2.6], 38.9% (33.2–44.9%) in HER2+/HR– [OR 7.1] and 31.1% (26.5–36.1%) in triple negative [OR 5.0]; pCR% was significantly higher for the HER2+/HR– compared with the triple negative subtype, however pCR% was very similar for these subtypes (and OR = 5.0 both subtypes) when studies using HER2-directed therapy with NAC were excluded from the model. Neither sensitivity analysis (excluding unknown subtypes), nor adjustment for associated covariates, substantially altered our findings.

Interpretation

This meta-analysis provides evidence of an independent association between breast cancer subtype and pCR; odds of pCR were highest for the triple negative and HER2+/HR– subtypes, with evidence of an influential effect on achieving pCR in the latter subtype through inclusion of HER2-directed therapy with NAC.

Section snippets

Background

Over the past decade, neoadjuvant (pre-operative) chemotherapy has emerged as the standard of care in the treatment of inoperable and operable locally advanced breast cancer.1, 2 Neoadjuvant chemotherapy (NAC) has also been increasingly used in operable breast cancer, where it has been shown to be as effective as adjuvant chemotherapy3 while offering potential advantages that include: downsizing the primary tumour with resulting conversion of mastectomy candidates to breast conserving surgery

Methods

We performed a study-level meta-analysis of studies reporting data that allow calculation of the proportion of subjects with pCR by tumour subtype in the NAC setting. Studies were systematically identified and considered eligible if they reported data for all breast cancer subtypes within the study cohort; studies declaring some subjects with unknown subtypes were eligible. We considered studies characterising tumour subtype on the basis of traditional markers [hormone receptor (HR: ER/PR, at

Results

Thirty primary studies4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 met our defined eligibility criteria, and provided data on 11,695 subjects in evidence synthesis (an additional paper2 provided supplementary data on five of these studies4, 6, 7, 8, 9 – Appendix 1). Characteristics of the 30 studies and descriptive analysis, including the distribution of covariates, are shown in Table 1. Study-specific median pCR% was 19.8%

Discussion

The biological heterogeneity of breast cancer has been known for decades, and has been confirmed in the recent decade in gene expression profiling studies that highlighted various intrinsic breast cancer subtypes.34 In this meta-analysis, we report summary estimates of pCR% for breast cancer subtype, defined by HR and HER2 status, given that pCR following NAC is an established surrogate end-point for prognosis. Furthermore, it appears likely that in the future the construct of conventional

Authors’ contributions

N.H. conceived the study idea, conducted the literature searches and review of studies, performed data extraction, interpreted analyses and drafted the manuscript; P.M. performed statistical analyses and advised on data interpretation, advised on methodological aspects and contributed to drafting the manuscript; G.v.M. advised on clinical content and on data resolution, provided additional data and contributed to drafting the manuscript; M.L.M. assisted with the literature searches and review

Conflict of interest statement

None declared.

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    ☆

    This work was partly funded by National Health and Medical Research Council (NHMRC) programme grant 633003 to the Screening & Test Evaluation Program.

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