PCR After Neoadjuvant Chemo and Breast Cancer Subtypes
PCR After Neoadjuvant Chemo and Breast Cancer Subtypes
This was a planned secondary analysis of the EORTC 10994/BIG 1-00 trial which randomized patients between six cycles of 5-fluorouracil, epirubicin and cyclophosphamide and a taxane-based regimen, docetaxel × three cycles followed by epirubicin + docetaxel for three cycles, all given before primary surgery Eligible patients were women aged <71 years with histologically proven invasive carcinoma of the breast suitable for neoadjuvant chemotherapy, with any large operable or locally advanced/inflammatory breast cancer. Patients with HER2-positive tumours were allowed to enter adjuvant clinical trials assessing trastuzumab or to receive this treatment in the adjuvant setting once it became standard practice, and none received neoadjuvant trastuzumab.
The trial was approved by national and/or local ethics committees in all participating centres. Before registration, all patients gave signed informed consent for the clinical trial and for research on tumour samples.
For the sub-study that is the subject of this report, a subgroup of the initial population of 1856 was selected based on the following criteria: (i) patients with sufficient information available on HER2, ER, PR (progesterone receptor) and tumour grade to permit a simplified intrinsic subtype classification as defined below; (ii) patients who received at least one cycle of neoadjuvant chemotherapy and who did not receive radiotherapy before surgery; (iii) patients without inflammatory cancers (T4d). The analysis including pathological response was further confined to patients with post-treatment pathology data and whose tumours did not progress on neoadjuvant chemotherapy.
The primary objective of this analysis was to assess the effect of pCR on event-free survival (EFS) by breast cancer intrinsic subtype (the simplified intrinsic subtypes classification used in this study is detailed in the pathology section below), in a two-step multivariate analysis adjusting for important factors prognostic for EFS, as listed in the statistical section.
Secondary objectives included investigating (i) the effect of TP53 function on pCR and survival outcomes within each subtype and (ii) the effect of treatment on survival outcomes across subtypes.
No central pathology review was carried out for this analysis. Grade, ER, PR and HER2 status were assessed by local pathologists from a biopsy taken at diagnosis and prospectively collected in the case report form. ER and PR, assessed by immunohistochemistry (IHC), were reported as positive or negative according to each centre's local definition. HER2 positivity was defined as either HER2 gene amplification by fluorescent in situ hybridization and/or scored 3+ by IHC. Because information on Ki-67 was not available from data collected within the main TP53 study, we replaced Ki-67 by grade in order to classify tumours in a simplified intrinsic subtype's classification, as suggested by the St Gallen 2011 consensus We used the following classification:
Pathological response was assessed by local pathologists after completion of the neoadjuvant chemotherapy. pCR was defined as no evidence of residual 'invasive cancer' or very few scattered tumour cells left in the primary breast tumour—with or without residual ductal carcinoma in situ (DCIS)—and in the lymph nodes. TP53 status was assessed using a functional test in yeast as previously described
A statistical analysis plan was prospectively defined. Eligible patients were analysed on an intent-to-treat basis. Associations between baseline characteristics and pCR were evaluated in a multivariate logistic regression model. Survival times were defined as time from randomization to an event.
In order to investigate the prognostic value of pCR on outcomes, a landmark analysis approach was used, with the landmark chosen as the date of surgery. Of note, by definition, patients who progressed on neoadjuvant treatment were excluded from this analysis. To address our research question, the following two-step approach was adopted after adjusting for important prognostic factors (supplementary Figure S1, available at Annal sof Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1): as a first-step, the potential effects of the three interactions (pCR and intrinsic subtypes; TP53 status and intrinsic subtypes; treatment arm and intrinsic subtypes) were simultaneously investigated in a multivariate Cox regression model, adjusting for age at diagnosis, menopausal status, cT stage, cN stage and tumour histology (invasive ductal, invasive lobular or other invasive carcinoma). Interactions with a P value of ≤0.1 were considered significant. When a significant interaction was observed, the HRs [99% confidence intervals (CI)] within the different subtypes were reported. If not, as a second-step, the multivariate model was refitted without interaction(s) and an overall (i.e. over all intrinsic subtypes) HR (99% CI) was reported. All non-interactions tests were compared with a significance level α = 0.01.
Methods
Study Design, Eligibility and Treatment
This was a planned secondary analysis of the EORTC 10994/BIG 1-00 trial which randomized patients between six cycles of 5-fluorouracil, epirubicin and cyclophosphamide and a taxane-based regimen, docetaxel × three cycles followed by epirubicin + docetaxel for three cycles, all given before primary surgery Eligible patients were women aged <71 years with histologically proven invasive carcinoma of the breast suitable for neoadjuvant chemotherapy, with any large operable or locally advanced/inflammatory breast cancer. Patients with HER2-positive tumours were allowed to enter adjuvant clinical trials assessing trastuzumab or to receive this treatment in the adjuvant setting once it became standard practice, and none received neoadjuvant trastuzumab.
The trial was approved by national and/or local ethics committees in all participating centres. Before registration, all patients gave signed informed consent for the clinical trial and for research on tumour samples.
For the sub-study that is the subject of this report, a subgroup of the initial population of 1856 was selected based on the following criteria: (i) patients with sufficient information available on HER2, ER, PR (progesterone receptor) and tumour grade to permit a simplified intrinsic subtype classification as defined below; (ii) patients who received at least one cycle of neoadjuvant chemotherapy and who did not receive radiotherapy before surgery; (iii) patients without inflammatory cancers (T4d). The analysis including pathological response was further confined to patients with post-treatment pathology data and whose tumours did not progress on neoadjuvant chemotherapy.
Objectives
The primary objective of this analysis was to assess the effect of pCR on event-free survival (EFS) by breast cancer intrinsic subtype (the simplified intrinsic subtypes classification used in this study is detailed in the pathology section below), in a two-step multivariate analysis adjusting for important factors prognostic for EFS, as listed in the statistical section.
Secondary objectives included investigating (i) the effect of TP53 function on pCR and survival outcomes within each subtype and (ii) the effect of treatment on survival outcomes across subtypes.
Pathology Assessment
No central pathology review was carried out for this analysis. Grade, ER, PR and HER2 status were assessed by local pathologists from a biopsy taken at diagnosis and prospectively collected in the case report form. ER and PR, assessed by immunohistochemistry (IHC), were reported as positive or negative according to each centre's local definition. HER2 positivity was defined as either HER2 gene amplification by fluorescent in situ hybridization and/or scored 3+ by IHC. Because information on Ki-67 was not available from data collected within the main TP53 study, we replaced Ki-67 by grade in order to classify tumours in a simplified intrinsic subtype's classification, as suggested by the St Gallen 2011 consensus We used the following classification:
Luminal A-like: ER and/or PR positive, HER2 negative and grade 1 or 2.
Luminal B-like (HER2 negative): ER and/or PR positive, HER2 negative and grade 3.
Luminal B-like (HER2 positive): ER and/or PR positive, HER2 positive (IHC3+ or amplified) and any grade (or grade unknown).
HER2 positive (non-luminal): ER and PR negative, HER2 positive (IHC3+ or amplified) and any grade (or grade unknown).
TN: ER and PR negative, HER2 negative and any grade (or grade unknown).
Pathological response was assessed by local pathologists after completion of the neoadjuvant chemotherapy. pCR was defined as no evidence of residual 'invasive cancer' or very few scattered tumour cells left in the primary breast tumour—with or without residual ductal carcinoma in situ (DCIS)—and in the lymph nodes. TP53 status was assessed using a functional test in yeast as previously described
Statistical Analysis
A statistical analysis plan was prospectively defined. Eligible patients were analysed on an intent-to-treat basis. Associations between baseline characteristics and pCR were evaluated in a multivariate logistic regression model. Survival times were defined as time from randomization to an event.
In order to investigate the prognostic value of pCR on outcomes, a landmark analysis approach was used, with the landmark chosen as the date of surgery. Of note, by definition, patients who progressed on neoadjuvant treatment were excluded from this analysis. To address our research question, the following two-step approach was adopted after adjusting for important prognostic factors (supplementary Figure S1, available at Annal sof Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1): as a first-step, the potential effects of the three interactions (pCR and intrinsic subtypes; TP53 status and intrinsic subtypes; treatment arm and intrinsic subtypes) were simultaneously investigated in a multivariate Cox regression model, adjusting for age at diagnosis, menopausal status, cT stage, cN stage and tumour histology (invasive ductal, invasive lobular or other invasive carcinoma). Interactions with a P value of ≤0.1 were considered significant. When a significant interaction was observed, the HRs [99% confidence intervals (CI)] within the different subtypes were reported. If not, as a second-step, the multivariate model was refitted without interaction(s) and an overall (i.e. over all intrinsic subtypes) HR (99% CI) was reported. All non-interactions tests were compared with a significance level α = 0.01.
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