New Model Accurately Predicts Relapse in Breast Cancer

Roxanne Nelson

September 24, 2008

September 24, 2008 — Neoadjuvant systemic therapy for breast cancer is increasingly used for patients with estrogen-receptor positive (ER+) stage 2 and 3 breast cancer to improve surgical outcomes, but factors predictive of relapse after treatment have not been identified.

However, a study published online September 23 in the Journal of the National Cancer Institute (JNCI) outlines a validated model that might help define patients at risk for relapse. The preoperative endocrine prognostic index (PEPI) might be able to identify patients at a very low risk for relapse and thus unlikely to benefit from adjuvant chemotherapy.

"This is the first time this result has been presented and so we do need to conduct new studies in this area," said lead author Mathew Ellis, MB, BChir, PhD, associate professor of medicine at Washington University School of Medicine in St. Louis, Missouri. "The data we report in JNCI will certainly make new studies of neoadjuvant endocrine therapy easier to do because patients will now be even more motivated, given the opportunity for treatment individualization and avoidance of unnecessary chemotherapy."

Dr. Ellis and colleagues note that developing an accurate test to predict the efficacy of adjuvant endocrine therapy for hormone-receptor-positive breast cancer, on an individual basis, would be an important therapeutic advance. But, compared with studies of neoadjuvant chemotherapy, there have been fewer trials evaluating neoadjuvant endocrine therapy and, therefore, fewer data are available to link postneoadjuvant therapy tumor characteristics to survival.

A large randomized trial, known as PO24, compared 4 months of treatment with neoadjuvant letrozole with 4 months of treatment with tamoxifen before surgery in postmenopausal women. The researchers used data from this study to develop a prognostic model that incorporates standard pathologic staging variables and "on-treatment" biomarker values. Tumor tissue from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancer who participated in the study was analyzed for posttreatment ER status, Ki67 proliferation antigen index, histologic grade, pathologic tumor size, node status, and treatment response.

Using Cox proportional hazards, the researchers identified factors associated with relapse-free survival and breast-cancer-specific survival in 158 women, and used these data to create PEPI. They then independently validated the PEPI model in 203 postmenopausal women who participated in the IMPACT study, another neoadjuvant endocrine therapy trial with short-term end points that were similar to those used in the PO24 trial.

The median follow-up period in the PO24 trial was 61.2 months. None of the patients who were confirmed at baseline with ER+ stage 2 and 3 tumors and who were downstaged to stage 1 or 0 at surgery relapsed. After multivariable testing of posttreatment tumor characteristics, the researchers noted that pathologic tumor size, node status, Ki67 level, and ER status were all independently associated with relapse-free survival and breast-cancer-specific survival.

The PEPI model that was developed on the basis of these factors predicted relapse-free survival in patients participating in the IMPACT study.

The authors write that it is of particular note that patients with stage 1 or 0 diseased and a favorable biomarker profile (a PEPI score of 0) at surgery experienced such a low rate of relapse "that further adjuvant systemic therapy beyond continuation of an endocrine agent appears unnecessary."

Conversely, patients with high-pathologic-stage tumors at surgery and a poor biomarker profile (a PEPI score of >4) had a statistically significant higher risk for early relapse and "therefore should be offered all appropriate adjuvant treatments available."

"I am personally convinced from the data that a patient with a pathologic stage 1 cancer and a PEPI score of 0 after neoadjuvant endocrine therapy is unlikely to benefit from chemotherapy, since not a single relapse was seen in either study in this group," Dr. Ellis told Medscape Oncology. "Physicians already instinctively knew this because the use of chemotherapy in this group of patients was very low — a decision they must have made at the time based on pathologic stage and perhaps clinical response to treatment."

"A further reason for my confidence is that the PEPI model is built on many years of research that confirms the importance of pathologic tumor stage, tumor growth rates, and estrogen-receptor expression," he added. "All that we have done here is to place this information in a new setting, where the influence of endocrine treatment on these parameters can be measured."

The researchers suggest that their biomarker analysis would benefit from retrospective studies of tumor samples from similar patients, but with a longer follow-up. Prospective validation of the model is warranted to confirm the PEPI model as a tool that could help guide individual treatment and assess novel endocrine therapies in future clinical trials.

J Natl Cancer Inst. 2008;100:1380-1388.

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