Midstream Chemo Switch May Improve Breast Cancer Survival

Neil Osterweil

December 09, 2011

December 9, 2011 (San Antonio, Texas) — Changing chemotherapy regimens midstream on the basis of individual patient responses to the first 2 cycles pays off with improved overall survival (OS) and disease-free survival (DFS) rates for patients with luminal-type breast cancers, according to a study reported here at the 34th Annual San Antonio Breast Cancer Symposium (SABCS).

But patients with HER2-positive or triple-negative (lacking HER2, estrogen, and progesterone receptors) tumors did not have a benefit from response-guided therapy, reported Gunther von Minckwitz, MD, PhD, professor and senior physician at the Center for Gynecology and Obstetrics at the University of Frankfurt in Frankfurt, Germany, on behalf of colleagues in the GEPAR-TRIO (GErman Pre-operative Adriamycin and Docetaxel) trial.

The trial also showed a disconnect between treatment effects and complete responses on pathology (pCR) in some disease subtypes, Dr. von Minckwitz said.

"Interim response-guided neoadjuvant chemotherapy improved survival. Treatment effects on survival derived from luminal-type tumors. This treatment effect could not be predicted by pCR as these tumors have lower pCR rates, and their prognosis does not depend on pCR," he said.

In contrast, for patients with HER2-positive or triple-negative tumors, for whom response-guided treatment was ineffective, pCR was highly prognostic, he said.

Breast cancer specialist Steven J. Isakoff, MD, PhD, from Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study, says the findings add to the body of evidence about the difficulties of treating triple-negative disease.

"What was concerning to me was that in patients with triple-negative disease, if you had a pathologic CR you did very well, and if you didn't, you did poorly. What was disheartening, and what we've seen in the past as well, is that changing treatment didn't seem to matter, and I think this highlights the challenges in treating this type of breast cancer," Dr. Isakoff said.

"There are a number of studies going on or being proposed in the triple-negative subgroup to evaluate people who didn't achieve a pathological CR, and to see whether giving additional chemotherapy after surgery would help."

"The concern, potentially, from a study like this is that this may be more a marker of general chemotherapy insensitivity rather than insensitivity to specific types of chemotherapy," he said in an interview with Medscape Medical News.

"That's a very frustrating position to be in — not having a response. You would like to be able to make a switch based on interim response if response is not especially favorable," Peter Ravdin, MD, PhD, codirector of the symposium at which the GEPAR-TRIO results were presented, told Medscape Medical News. Dr. Ravdin is director of the Comprehensive Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.

Study Details

The GEPAR-TRIO trial was designed to examine the effect of basing neoadjuvant chemotherapy choices on clinical and pathologic responses after 2 cycles of the TAC regimen (docetaxel, doxorubicin, and cyclophosphamide).

A total of 2072 women with operable or locally advanced breast cancer were assigned to 2 cycles of TAC and then randomly assigned according to their clinical course. Patients with a CR or partial response (PR) were randomly assigned to receive 4 additional cycles of TAC followed by surgery (TACx6) or 6 additional cycles plus surgery (TACx8).

Patients who did not have a response of more than 50% reduction in tumor volume were considered nonresponders and were randomly assigned to TACx6 or to 4 cycles of vinorelbine and capecitabine (NX) before surgery.

Short-term efficacy results from the trial were published in 2008.

Dr. von Minckwitz presented data on the secondary objective of the trial, which was to determine DFS and OS at 5 years (62-month median follow-up), and from a post hoc analysis looking at the treatment effects by breast cancer phenotype.

In all, 1025 patients received conventional therapy (TACx6), and 987 received response-guided therapy (TACx8 or TAC-NX).

Among all patients, those who received response-guided therapy fared better than those who received conventional treatment in both DFS (hazard ratio [HR] for response-guided therapy, 0.71; 95% confidence interval [CI], 0.60 - 0.85; P < .001) and OS (HR, 0.79; 95% CI, 0.63 - 0.99; P = .048). A lower HR indicates prolonged DFS.

In an adjusted analysis, significant contributors to better DFS included response-guided treatment (HR, 0.71; P = .001), stage cT1-3 (HR, 0.60; P < .001), negative nodal status (HR, 0.56; P < .001), and hormone receptor positivity (HR, 0.49; P < .001).

Among responders, response-guided therapy with TACx8 was slightly but significantly better for prolonging DFS (HR for TACx8, 0.78; 95% CI, 0.62 - 0.97; P = .026).

Among nonresponders, response-guided treatment was also significantly better for DFS than conventional therapy (HR, 0.59; 95% CI, 0.49 - 0.82; P = .001).

A subgroup analysis comparing DFS after conventional vs response-guided treatment showed no effects for age group, stage, histologic type, or grade.

When they looked at hormone receptor status, however, the investigators found that hormone receptor–positive tumors had an HR of 0.56 (95% CI, 0.44 - 0.73), but there was no effect of treatment type on hormone receptor–negative tumors (HR, 0.94; 95% CI, 0.73 - 1.22).

"When we go further in depth and look for separate phenotypes, all of the luminal tumors had a treatment effect with response-guided treatment, whereas the HER2-positive and HER2-negative tumors did not. We therefore started to look more in detail why the pCR rates did not predict these long-term outcome results," Dr. von Minckwitz said.

The investigators looked at pCR rates, at the prognostic effect of pCR rates on outcomes, and the treatment effects on outcomes for each of the different tumor subtypes, grouped according to the St. Gallen definition.

An analysis of pCR rates by subtypes showed that luminal A tumors had a 5% pCR rate, compared with 18% for luminal B (HER2-) tumors, and 9.5% for luminal B (HER2+) tumors. Pathologic CR was 28% for HER2+ nonluminal tumors and 37% for triple-negative lesions.

When the GEPAR-TRIO team looked at luminal A tumors, there was no significant difference in DFS by pCR, but they did note a significant difference in treatment type favoring response-guided treatment (HR, 0.55; 95% CI, 0.36 - 0.82; P = .003).

Among patients with luminal B (HER2-) disease, pCR significantly predicted better DFS (HR for predicting DFS, 3.74; 95% CI, 1.15 - 12.1; P = .018), and response-guided treatment was better at prolonging time to progression (HR, 0.40; P = .006).

In luminal B (HER2+) tumors, pCR had no predictive value, but response-guided treatment was significantly better at improving DFS (HR, 0.56; 95% CI, 0.33 - 0.97; P = .035).

In contrast, for patients with DFS HER2+ (nonluminal) tumors, pCR had good prognostic value (HR, 5.24; 95% CI, 2.25 - 12.1), but there was no significant treatment-type effect.

Similarly, pCR was prognostic for DFS in patients with triple-negative breast cancer (HR, 6.67; 95% CI, 3.61 - 11.9; P = .001), but there was no significant treatment effect.

The study was supported by Amgen, Roche, and sanofi-aventis. Dr. von Minckwitz disclosed that he receives grant support from sanofi-aventis, Roche, GlaxoSmithKline, and Novartis and is on the speakers' bureau for Roche. Dr. Isakoff has disclosed no relevant financial relationships. Dr. Ravdin has disclosed that he is a board member/officer/trustee and owner of Adjuvant, Inc.

34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-2. Presented December 8, 2011.

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