Meta-analysis of Breast Cancer Studies Demonstrates Value of Pathologic Complete Response


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The prognostic significance of pathologic complete response after neoadjuvant chemotherapy remains unclear, particularly for hormone receptor–positive and HER2-positive breast cancer, where adjuvant therapy after surgery could also have an impact on survival.
— Laura Spring, MD

In a meta-analysis of neoadjuvant studies totaling over 18,000 patients, achievement of pathologic complete response was associated with significantly reduced disease recurrence and mortality across the various breast cancer subtypes. Laura Spring, MD, a senior medical oncology fellow at Massachusetts General Hospital, Boston, received a Scholar-in-Training Award for this work at the 2016 American Association of Cancer Research (AACR) Annual Meeting, where the results were presented.1

She and her colleagues conducted the meta-analysis because, as noted by the authors, “The prognostic significance of pathologic complete response after neoadjuvant chemotherapy remains unclear, particularly for hormone receptor–positive and HER2-positive breast cancer, where adjuvant therapy after surgery could also have an impact on survival.”

Study Details

Dr. Spring and colleagues identified 49 eligible studies totaling 18,772 patients. Both clinical trials and retrospective studies were included to capture a more comprehensive patient population. All studies reported pathologic complete response results as well as recurrence and/or mortality rates, stratified by the presence or absence of pathologic complete response. The majority of studies featured patients with stages II–III disease and defined pathologic complete response as no invasive residual disease in the breast or nodes. In these studies, neoadjuvant therapy was chemotherapy, as well as HER2-directed therapy in a subset of patients; patients with hormone receptor–positive disease did not receive endocrine therapy preoperatively.

Pathologic Complete Response as Surrogate Marker of Outcomes

  • A meta-analysis of 49 neoadjuvant studies involving 18,772 patients showed that achievement of pathologic complete response is associated with substantial reductions in recurrence and mortality.
  • The overall pathologic complete response rate was 21.5%, with the highest rate among subtypes being 70.3% in HER2-positive disease.
  • Pathologic complete response was associated with reductions in recurrence of more than 60% and in mortality of more than 70%.

Altogether, the rate of pathologic complete response was 21.5%, and patients who achieved pathologic complete response had an odds ratio of 0.33 (confidence interval [CI] = 0.28–0.39; P < .001) for recurrence and 0.28 for mortality (CI = 0.21–0.36; P < .001) the analysis found. The following pathologic complete response rates were found for the three main breast cancer subtypes: hormone receptor–positive disease, 8.3%; HER2-positive disease, 70.3%; and triple-negative disease, 38.7%. In all three subtypes studied, achievement of pathologic complete response was associated with significantly reduced disease recurrence and mortality.

“While hormone receptor–positive tumors are less likely to achieve pathologic complete response as compared to triple-negative or HER2-positive tumors, when present, pathologic complete response was associated with significantly lower disease recurrence and mortality in our study,” Dr. Spring pointed out.

However, patients with hormone receptor–positive tumors generally receive adjuvant endocrine therapy, which can lower the risk of recurrence, even in the absence of pathologic complete response, she elaborated. “In contrast, I am more concerned about patients with triple-negative breast cancer who do not achieve a pathologic complete response, since they have more limited therapy options and in general have a worse prognosis,” Dr. Spring explained.

Surrogate Marker

Dr. Spring and her colleagues recently performed a meta-analysis on neoadjuvant endocrine therapy in hormone receptor–positive women (results presented at the 2015 San Antonio Breast Cancer Symposium).2 “Given the relatively low toxicity with this approach compared to chemotherapy, we argue that neoadjuvant endocrine therapy should be considered more often, particularly when combined with novel targeted agents in the clinical trial setting,” she added.

Aditya Bardia, MBBS, MPH

Aditya Bardia, MBBS, MPH

“Our results provide support for utilization of pathologic complete response as a surrogate marker for survival outcomes as newer targeted therapies are evaluated in the neoadjuvant setting, as witnessed by the U.S. Food and Drug Administration’s accelerated approval of neoadjuvant pertuzumab (Perjeta) based on pathologic complete response as an endpoint in 2013,” commented Aditya Bardia, MBBS, MPH, senior author of the study and attending physician at Massachusetts General Hospital Cancer Center, Harvard Medical School. He further points out the use of pathologic complete response as a surrogate endpoint might provide an “efficient” model for drug development in localized breast cancer.3,4

Disclosure: Dr. Spring reported no potential conflicts of interest. Dr. Bardia is a consultant or has served on advisory boards for Novartis.

References

1. Spring L, Greenup R, Reynolds K, et al: Pathological complete response after neoadjuvant chemotherapy predicts improved survival in all major subtypes of breast cancer: Systematic review and meta-analyses of over 18,000 patients. 2016 AACR Annual Meeting. Abstract 1439. Presented April 18, 2016.

2. Spring L, Gupta A, Reynolds K, et al: Neoadjuvant endocrine therapy for estrogen receptor positive breast cancer: Comprehensive systematic review and meta-analysis. 2015 San Antonio Breast Cancer Symposium. Presented December 11, 2015.

3. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.

4. Bardia A, Baselga J: Neoadjuvant therapy as a platform for drug development and approval in breast cancer. Clin Cancer Res19:6360-6370, 2013.



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