More 'Promacs,' Worse Outcome

March 1, 2007

Proliferating macrophages (promacs) in invasive breast tumors predict worse outcomes and are particularly frequent in breast cancers from women in West Africa

SAN ANTONIO—Proliferating macrophages (promacs) in invasive breast tumors predict worse outcomes and are particularly frequent in breast cancers from women in West Africa, Laura Esserman, MD, MBA, of the University of California, San Francisco, reported at the 29th Annual San Antonio Breast Cancer Symposium (abstract 7). Macrophages, key cells in the inflammatory cascade, have been associated with invasion and metastases. Increasing numbers of macrophages per high power field (HPF) have been shown to correlate with poor prognosis. In animal models, macrophage growth factor has been shown to play a key regulatory role, secreting epidermal growth factor (EGF) and stimulating EGFR-positive tumors.

Dr. Esserman's research group previously found that proliferating macro-phages were abundant in large palpable ductal carcinoma in situ (Esserman et al: J Clin Oncol 24:4603-4610, 2006), particularly in areas of necrosis and among ductal cells. The current study presented at San Antonio extended these observations to invasive breast cancer.

The dataset was based on paraffin sections of invasive tumors from 110 patients who were followed for a median of 8.5 years, and microarrays from 43 breast cancer cases from West Africa. Samples were double-stained with PCNA, a proliferation marker, and CD68, a macrophage marker. The number of promacs/HPF were counted by two independent pathologists, with good concordance, and tumor grade was reassessed. Outcomes were available for the US cases, and Kaplan-Meier survival curves were generated.

The presence of promacs was associated with tumor grade. Promacs ≥ 5/HPF were found in 28% of grade 1 tumors, 41% of grade 2 tumors, and 68% of grade 3 tumors. "Promacs ≥ 5/HPF predict poor outcomes, independent of treatment," Dr. Esserman said, "and are, in fact, a marker of decreased survival."

For the population of patients with promacs < 5/HPF, survival at nearly 9 years was greater than 75%, compared with approximately 50% for the subset with ≥ 5/HPF (P = .02). In a multivariate analysis (size, age, grade, hormone-receptor status, palpability, stage, promac number), stage and promacs ≥ 5/HPF were the best predictors of recurrence (see Table) (HER2 status was not included). The predictive model was highly significant (P < .002), and therapy did not affect the impact of promacs ≥ 5/HPF, she said.

The persistence of promacs had its greatest impact on survival in the higher-stage, higher-grade tumors. Survival was similar in stage I patients, regardless of promac count. For stage II and III patients, long-term survival was approximately 75% for patients with promacs < 5/HPF, but dropped to around 40% for patients with promacs ≥ 5/HPF. Patients with grade 3 tumors had nearly a sixfold increased risk of mortality (P = .02) with promacs ≥ 5/HPF, while grade 1 and 2 tumors were not significantly affected by promac count, Dr. Esserman reported.

Based on information on 62 patients, the researchers found that promacs ≥ 5/HPF were not confined to the HER2-positive subset but were equally or more likely to be found in HER2-negative tumors, especially those of higher grade.

Cancer in West Africa

A collaboration with an investigator in West Africa, Dr. Olofunmilayo Olopade, allowed for comparison between US cases and those of West African women. "Breast cancer in West Africa tends to present in later stages and in younger women. These tumors are largely ER negative, often arise and progress rapidly, have very poor outcomes, and are not well understood," she noted. Based on the findings from her study, Dr. Esserman suggested that the higher frequency of promacs ≥ 5/HPF in these tumors may partly explain the more aggressive nature of cases in West Africa.

Tumor microarrays for 40 West African tumors showed that 95% of tumors contained promacs ≥ 5/HPF, compared with 42% of the US cases.

"The genesis of promacs is not clear. They could be triggered by an external event, such as a viral infection, and become intrinsic to the disease process. They could be generated by a specific tumor type, and there could be inherent differences in susceptibility," she proposed. [See also Dr. Tripathy's Vantage Point.]

Dr. Esserman and her colleagues are exploring the association of promacs with human mammary tumor virus (HMTV) [see Dr. Holland's report, page 33]; evaluating peripheral blood macrophages as potential markers for promac-positive tumors; and investigating the use of promacs as therapeutic targets.