Trastuzumab and Survival in Breast Cancer
Trastuzumab and Survival in Breast Cancer
The addition of trastuzumab to anthracycline and taxane-based chemotherapy in the neoadjuvant setting among women with HER2-positive breast cancer has resulted in pCR rates ranging from 32% to 66% and improvements in event-free survival. In this study, we report the long-term benefit of achieving a pCR. Specifically, pCR was a significant predictor of DMFS, RFS, and OS. Moreover, an increased risk of recurrence and death was seen among patients with increasing burden of remaining disease after neoadjuvant therapy. After controlling for disease- and treatment-related factors, achieving a pCR was the strongest predictor of long-term outcome.
Our results are consistent with data from the TECHNO trial, a phase II non-randomized study of 217 patients with HER2-overexpressing disease who received 6 months of neoadjuvant epirubicin and paclitaxel-based (Bristol-Myers Squibb, New York) chemotherapy and trastuzumab. In this trial, pCR was achieved in 39%. Disease-free and OS outcomes were superior among patients achieving a pCR compared with those with less than pCR, and pCR was the strongest prognostic factor for relapse and death. Locoregional and distant patterns of relapse were not described in that study. Similarly, in our study, we found that achieving a pCR was the strongest predictor of long-term disease control and survival, even after controlling for various disease and treatment-related factors. In addition, locoregional and distant relapse rates were encouragingly low after a median follow-up of 5 years.
Our study highlights the complex interplay between tumor biology, treatment response, and long-term clinical outcome. In our series, neoadjuvant trastuzumab-containing chemotherapy was effective in eradicating invasive disease in nearly 50% of patients and in our multivariate model, pCR retained a strong association with survival, even after controlling for standard clinical and pathologic prognostic factors. For patients not achieving a pCR, we found an inverse relationship between residual disease, as indicated by pathologic stage, and long-term disease control and survival. In the subset of patients with residual DCIS after neoadjuvant therapy, no differences in distant metastasis and OS outcomes were noted compared with those achieving eradication of invasive and non-invasive disease in the breast and axilla. This is consistent with a recent meta-analysis of 12 randomized neoadjuvant chemotherapy trials. This analysis found that 13% of patients had a pCR defined as no residual invasive disease in the breast or axilla and 18% had a pCR defined as no residual invasive or in situ disease in the breast. A pCR by either definition predicted for improved event-free survival and OS. These data and our results are in contrast to a study by von Minckwitz et al. that evaluated over 6000 patients enrolled on seven prospective trials of neoadjuvant chemotherapy and showed that patients with residual DCIS in the breast did worse with respect to disease-free survival and trended towards worse OS. In subset analyses evaluating 622 patients with HER2-positive disease that received trastuzumab as part of their neoadjuvant chemotherapy, a pCR defined as no residual invasive disease or DCIS in the breast and axillary lymph nodes was associated with improved disease-free and OS. Although a higher percentage of patients with hormone receptor-negative tumors in our study achieved a pCR than those with hormone receptor-positive disease as seen in other studies, no interaction between hormone receptor status and pCR on distant metastasis, disease relapse, or OS was seen, highlighting the prognostic significance of pCR on long-term outcome independent of hormone receptor status. In addition, whether trastuzumab was delivered in the neoadjuvant setting alone or continued for 1 year did not impact relapse and survival outcomes in our study.
Limitations of this study include its retrospective design that did not permit the assessment of independent causality between pathologic response and outcome. Among the strengths of this study include specialized pathology review of all cases, consistent multidisciplinary care and median follow-up greater than 5 years during which most of the recurrences have been shown to occur in patients with HER2-overexpressing breast cancer.
In conclusion, achievement of pCR among patients with HER2-overexpressing breast cancer was the strongest predictor of disease control and survival. Given recent success of combined HER2-directed therapies in the neoadjuvant setting achieving even higher pCR rates, a greater benefit on long-term outcome would be predicted with this strategy. These findings underscore the potential value of pathologic response as an early surrogate of long-term outcome, and an important metric for future studies evaluating new HER2-targeted therapies. Consistent with this, the Food and Drug Administration has proposed using pCR as a surrogate end point, allowing for accelerated approval of therapeutics. Such an approach would allow for the most promising investigational drugs to be rapidly incorporated into treatment algorithms maximizing benefit for breast cancer patients with high-risk disease.
Discussion
The addition of trastuzumab to anthracycline and taxane-based chemotherapy in the neoadjuvant setting among women with HER2-positive breast cancer has resulted in pCR rates ranging from 32% to 66% and improvements in event-free survival. In this study, we report the long-term benefit of achieving a pCR. Specifically, pCR was a significant predictor of DMFS, RFS, and OS. Moreover, an increased risk of recurrence and death was seen among patients with increasing burden of remaining disease after neoadjuvant therapy. After controlling for disease- and treatment-related factors, achieving a pCR was the strongest predictor of long-term outcome.
Our results are consistent with data from the TECHNO trial, a phase II non-randomized study of 217 patients with HER2-overexpressing disease who received 6 months of neoadjuvant epirubicin and paclitaxel-based (Bristol-Myers Squibb, New York) chemotherapy and trastuzumab. In this trial, pCR was achieved in 39%. Disease-free and OS outcomes were superior among patients achieving a pCR compared with those with less than pCR, and pCR was the strongest prognostic factor for relapse and death. Locoregional and distant patterns of relapse were not described in that study. Similarly, in our study, we found that achieving a pCR was the strongest predictor of long-term disease control and survival, even after controlling for various disease and treatment-related factors. In addition, locoregional and distant relapse rates were encouragingly low after a median follow-up of 5 years.
Our study highlights the complex interplay between tumor biology, treatment response, and long-term clinical outcome. In our series, neoadjuvant trastuzumab-containing chemotherapy was effective in eradicating invasive disease in nearly 50% of patients and in our multivariate model, pCR retained a strong association with survival, even after controlling for standard clinical and pathologic prognostic factors. For patients not achieving a pCR, we found an inverse relationship between residual disease, as indicated by pathologic stage, and long-term disease control and survival. In the subset of patients with residual DCIS after neoadjuvant therapy, no differences in distant metastasis and OS outcomes were noted compared with those achieving eradication of invasive and non-invasive disease in the breast and axilla. This is consistent with a recent meta-analysis of 12 randomized neoadjuvant chemotherapy trials. This analysis found that 13% of patients had a pCR defined as no residual invasive disease in the breast or axilla and 18% had a pCR defined as no residual invasive or in situ disease in the breast. A pCR by either definition predicted for improved event-free survival and OS. These data and our results are in contrast to a study by von Minckwitz et al. that evaluated over 6000 patients enrolled on seven prospective trials of neoadjuvant chemotherapy and showed that patients with residual DCIS in the breast did worse with respect to disease-free survival and trended towards worse OS. In subset analyses evaluating 622 patients with HER2-positive disease that received trastuzumab as part of their neoadjuvant chemotherapy, a pCR defined as no residual invasive disease or DCIS in the breast and axillary lymph nodes was associated with improved disease-free and OS. Although a higher percentage of patients with hormone receptor-negative tumors in our study achieved a pCR than those with hormone receptor-positive disease as seen in other studies, no interaction between hormone receptor status and pCR on distant metastasis, disease relapse, or OS was seen, highlighting the prognostic significance of pCR on long-term outcome independent of hormone receptor status. In addition, whether trastuzumab was delivered in the neoadjuvant setting alone or continued for 1 year did not impact relapse and survival outcomes in our study.
Limitations of this study include its retrospective design that did not permit the assessment of independent causality between pathologic response and outcome. Among the strengths of this study include specialized pathology review of all cases, consistent multidisciplinary care and median follow-up greater than 5 years during which most of the recurrences have been shown to occur in patients with HER2-overexpressing breast cancer.
In conclusion, achievement of pCR among patients with HER2-overexpressing breast cancer was the strongest predictor of disease control and survival. Given recent success of combined HER2-directed therapies in the neoadjuvant setting achieving even higher pCR rates, a greater benefit on long-term outcome would be predicted with this strategy. These findings underscore the potential value of pathologic response as an early surrogate of long-term outcome, and an important metric for future studies evaluating new HER2-targeted therapies. Consistent with this, the Food and Drug Administration has proposed using pCR as a surrogate end point, allowing for accelerated approval of therapeutics. Such an approach would allow for the most promising investigational drugs to be rapidly incorporated into treatment algorithms maximizing benefit for breast cancer patients with high-risk disease.
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