With Upfront pCR, Some Patients May Skip Adjuvant Chemo

Breast cancer study confirms benefits of pathologic complete response

  • by Senior Associate Editor, MedPage Today

SAN ANTONIO -- Breast cancer patients who achieved a pathologic complete response (pCR) with neoadjuvant chemotherapy lived just as long with or without additional adjuvant chemotherapy, according to a meta-analysis involving almost 28,000 patients.

As previously shown by multiple studies, pCR after neoadjuvant therapy significantly improved event-free survival (EFS) and overall survival (OS), as compared with patients who did not attain pCR. However, the results also showed that patients who received adjuvant chemotherapy after pCR with neoadjuvant therapy had a 5-year EFS rate of 86% vs 88% for those who received no adjuvant systemic therapy. Similar results emerged from an analysis of OS.

The observations came with caveats: The magnitude of the benefit with pCR hinged on the definition of pCR and subsequent computer modeling. Additionally, about 80% of the patients included in the analysis did not achieve a pCR, as reported at the San Antonio Breast Cancer Symposium.

"The similar outcomes with or without adjuvant chemotherapy in patients who attain pathologic complete response after neoadjuvant chemotherapy likely reflects tumor biology and suggests that adjuvant chemotherapy could potentially be omitted in certain circumstances," said Laura M. Spring, MD, of Massachusetts General Hospital Cancer Center in Boston. "Further research is needed to evaluate the clinical utility of escalation/de-escalation strategies in the adjuvant setting based on neoadjuvant response."

"I think this supports strategies where you maybe use less cytotoxic chemotherapy and try to identify that group that will have a pCR with a de-escalation and then you can spare them, hopefully, additional cytotoxic chemotherapy," she added.

The take-home message for Carlos Arteaga, MD, of UT Southwestern Medical Center in Dallas, is that the impact of chemotherapy appears to occur early.

"If you use it early, you really don't lose the impact if you wait until after surgery," said Arteaga, who moderated a press briefing where Spring summarized the findings. "If it was me, I would have [chemotherapy] before the operation, frankly, because at a minimum it is not worse than delaying it until after surgery."

"And you get the potential benefit of breast conservation," he added.

Although the prognostic significance of pCR after neoadjuvant chemotherapy is well established, the impact of subsequent adjuvant therapy in modulating the association between pCR and long-term outcomes is less clear, Spring said in the introduction to her presentation. Moreover, the magnitude of the pCR change and corresponding change in long-term outcomes has not been established.

Those unknowns provided the basis for the meta-analysis, which included 52 published studies and 27,895 patients. The analysis included only studies that had a minimum of 25 patients, reported pCR results (ypT0 ypN0 or ypT0is ypN0), and reported recurrence and/or survival on the basis of pathologic outcome. Using computer modeling, the investigators estimated associations between pCR and EFS/OS, estimated EFS and OS, and evaluated the association between EFS and change in pCR.

Consistent with previous studies, the analysis showed that patients who attained a pCR with neoadjuvant therapy had a 69% improvement in EFS and a 78% improvement in OS, as compared with patients who had residual disease. Overall, pCR was associated with a 5-year EFS of 88% vs 67% and 5-year OS of 94% vs 75% for patients who had residual disease after neoadjuvant therapy.

Analyses by tumor subtype showed a consistent benefit in 5-year EFS for pCR vs residual disease: 90% vs 57% for triple-negative breast cancer, 86% vs 63% for HER2+ disease, and 97% vs 88% for HR+/HER2- breast cancer. Similar results came from analyses of OS.

Sharp and colleagues evaluated the impact of adjuvant chemotherapy within the context of pCR. They found that patients who attained a pCR with neoadjuvant therapy had a 5-year EFS of 86% with adjuvant chemotherapy and 88% without. The analysis showed that pCR led to significantly better EFS that was also comparable among patients who received adjuvant chemotherapy than those who did not (HR 0.36 for both groups).

Assuming that pCR is a valid surrogate marker and that an average pCR is 50%, the investigators examined the relationship between change in pCR and EFS. Across the range of changes in pCR from 0.1 to 1.0, there were corresponding declines in the EFS hazard ratio of 0.90 to 0.31, all associated with non-overlapping confidence intervals.

As an example, Sharp referenced the CALGB 40603 trial, which showed a 13% absolute improvement in pCR with the addition of carboplatin to standard chemotherapy. According to the statistical model, that change in pCR would correspond with an EFS hazard ratio of 0.87 (95% CI 0.84-0.89). In CALGB 40603, the carboplatin arm had an EFS of 0.84 vs the control arm, but the difference did not achieve statistical significance (95% CI 0.58-1.22).

The invited discussant for the study, Joseph Sparano, MD, of Montefiore Medical Center in Bronx, New York, said the meta-analysis "confirmed what we knew before" -- that pCR is associated with improved outcomes -- but with supporting data from far more patients. The lack of benefit with additional adjuvant chemotherapy in patients who attain pCR with neoadjuvant therapy is new information, as is the model to project EFS improvement associated with improved pCR rates, he said.

How pCR is defined is a key issue that can influence results, Sparano added. Moreover, large changes in pCR (>20%) are required to achieve clinically meaningful improvements in EFS.

Spring disclosed relationships with Novartis and Tesaro.