Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657

Abstract

Purpose: Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers.

Patients and methods: Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets.

Results: In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets.

Conclusion: In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.

Fig 1.

I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) schema. Sixteen-gauge core-needle biopsies were performed at four time points: T1, before treatment; T2, between 24 and 96 hours after starting treatment; T3, after completing the regimen that contained doxorubicin (if a taxane was to be given); and T4, at the time of surgical resection. Blood was drawn to obtain serum and plasma before chemotherapy, between anthracycline and taxane regimens, if applicable, and before surgery. Magnetic resonance (MR) images were obtained before chemotherapy, approximately 2 weeks after the first dose of anthracycline, at the end of anthracycline treatment (if the patient went on to receive a taxane), and again before surgical resection. The goal of the trial was to relate early and late outcomes. Early outcome measures included MR volume change and rates of pathologic complete response (pCR). Late outcomes were measured by recurrence-free survival (RFS), which was measured as the proportion of patients who did not experience an invasive breast cancer recurrence in the ipsilateral breast or regional nodes, distant organ sites, or death from any cause for the specified time period. MRI, magnetic resonance imaging. (*) Twenty-four to 96 hours after the start of anthracycline. (†) Two weeks after the start of anthracycline.

Fig 2.

I-SPY 1 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) CONSORT diagram. Of the 237 patients enrolled, 221 patients were evaluable, 215 had pathology results, and 210 had receptor data available. HER2, human epidermal growth factor receptor; HR, hormone receptor. (*) No. of patients who did not receive neoadjuvant trastuzumab. Trastuzumab was approved for use during the last year of study enrollment and was available to HER2-positive patients after that time. (†) No. of patients who did not receive any trastuzumab.

Fig 3.

Recurrence-free survival stratified by pathologic complete response (pCR) for the overall population (left side) of patients (excluding all patients treated with trastuzumab; n = 38) and (right side) by hormone receptor (HR) –positive/human epidermal growth factor receptor 2 (HER2) –negative, HR-negative/HER2-negative (triple negative), and HER2-positive subsets.