The 70-gene MammaPrint assay has been retrospectively validated as a prognostic tool, suggesting that younger breast cancer patients with intrinsically low-risk disease can be molecularly identified and that this information can be combined with clinical risk profiling to more accurately identify patients who might be spared adjuvant chemotherapy with its associated toxicity (10
). Most patients with breast cancer, however, are older and have comorbid disease that complicates decisions about the use of adjuvant chemotherapy. The potential role of the MammaPrint assay in the clinical care of these patients remains unclear.
We studied the 70-gene signature in an older breast cancer cohort who were diagnosed and treated at the MGH, purposely focusing on patients with lymph node–negative disease like those with whom MammaPrint was initially discovered and validated (9
). These MGH patients had a median age of 62.5 years with predominantly small and low-grade tumors. Forty-five percent of MGH patients also received some form of systemic treatment, reflecting known practice patterns among U.S. oncologists. Consistent with these differences, the MGH cohort had low distant recurrence rates.
The 70-gene signature displayed a remarkably high NPV (100%) in this cohort, which is consistent with earlier findings in younger cohorts (10
). Interestingly, MammaPrint-based classification also seemed to provide additive information to Adjuvant! Online–based risk determination. Although the MammaPrint assay was originally designed to identify younger breast cancer patients at low risk for distant metastasis who might consequently be spared systemic treatment, these results show that the same signature might identify older breast cancer patients at lower risk for distant recurrence at initial diagnosis.
In contrast, the MammaPrint assay had an extremely low PPV (12%), significantly lower than that previously observed in node-negative NKI patients (52%), thus resulting in statistically insignificant differences in overall survival between low- and high-risk patients. Remarkably, 73% of MGH patients were classified as high risk (including all nine patients who eventually developed metastasis), which was strikingly discordant with the low overall metastasis rate in this cohort (9%).
Because 45% of all patients received some adjuvant treatment, this discrepancy between molecular classification and clinical outcome could in part be explained by the significant use of adjuvant treatment in these patients. However, the proportional risk reduction for recurrent disease from adjuvant chemotherapy has been estimated to be ~ 20%, and for hormonal therapy ~ 30%, in postmenopausal patients (1
). Thus, even in the complete absence of adjuvant treatment, the event rate in the MGH cohort would likely only have doubled to ~ 18%, still far below what might be predicted through molecular classification with the MammaPrint assay.
This finding that the 70-gene signature molecularly classifies a significant percentage of older age breast cancer patients as “high risk,” of which few develop metastatic disease, may offer insight into the process of metastases. Following Paget’s hypothesis that metastasis depends both on the “seed” (the cancer cell itself) and the “soil” (the “host”), our findings raise the intriguing hypothesis that most breast cancers in older patients are intrinsically high risk but that this intrinsic metastatic capacity does not become manifest due to other (possibly host) factors in these predominantly postmenopausal patients.
Because older women with newly diagnosed breast cancer are increasingly being offered adjuvant treatment, in contrast with historical practice patterns, larger studies of the 70-gene signature should be done to determine whether the MammaPrint assay (with its excellent NPV) is clinically useful for pretreatment determination of intrinsic risk in older breast cancer patients. An open question in light of the poor PPV of MammaPrint in older patients is whether there exist additional, clinically useful gene expression signatures for positively predicting distant metastasis risk in the postmenopausal breast cancer population. Clearly, larger studies on postmenopausal breast cancer cohorts will be required to address this issue.