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Path CR signals good outcomes in treated high-risk breast cancers



SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

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