“The identification of the Luminal A group could lead to improved treatment,” said Dr. Glück “Molecular subtyping shows the potential of precision medicine in early breast cancer therapy. In this study, the advantages of molecular subtyping allowed us to identify both patients who could avoid chemotherapy prior to surgery, and those for whom chemotherapy provides a benefit.”3
The team’s retrospective analysis of data from 437 patients with breast cancer who had participated in four clinical trials revealed that 90 (21%) women who exhibited “little if any” benefit from chemotherapy, but who had good 5-year outcomes after surgery, could be detected with molecular assay–based subtyping—but not traditional clinical pathology, they reported. The team also reported that these patients can avoid chemotherapy, and instead receive neoadjuvant and adjuvant endocrine therapy alone.
“One of the potential benefits of molecular subtyping of breast cancers is that it may reduce the relative subjectivity of histopathological assessment,” report Dr. Alizart and colleagues.1 To achieve that promise and translate molecular subtyping into a routine diagnostic approach in the clinical setting, these tools need to be better standardized.1
“There is considerable variability depending on the total number of tumors analyzed,” Dr. Alizart and colleagues caution. “Careful micro-dissection” of tumors is required to avoid contamination of sequenced tumor tissue with normal epithelial or stromal breast cells, for example.1
The 70-gene prognostic MammaPrint expression array predicts distant metastasis and chemotherapy responses more accurately than clinicopathologic assessments alone, Dr. Alizard’s team readily acknowledges.1 However, MammaPrint was derived from “a relatively small cohort of patients” (younger than age 55 years) harboring tumors smaller than 5 cm in diameter, and with “diverse adjuvant therapy use” histories, they pointed out.1
Trials in Progress
The published evidence base for MammaPrint is largely retrospective in nature. On the other hand, the prospective observational RASTER (MicroarRAy prognoSTics in breast cancER; ISRCTN71917916) study of 427 patients in the Netherlands found a 5-year recurrence-free survival rate of 98% for patients who were MammaPrint-categorized as low-risk for metastasis, despite being deemed high risk based on age and clinicopathological variables.4
A multi-institutional, prospective, phase 3 clinical trial, MINDACT (Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy; NCT00433589), comparing the 70-gene signature with the common clinical-pathological criteria in selecting patients for adjuvant chemotherapy in breast cancer with 0-3 positive nodes, is also under way.4
Another trial, TAILORx (Trial Assigning IndividuaLized Options for Treatment [Rx]), is similarly testing Oncotype DX, another genomic panel that has been shown to be more predictive for patient prognosis than patient age, tumor size, or histological tumor grade.1
If phase 3 clinical trials confirm the promise of these and other molecular subtyping panels, a new age of more precise tumor classification seems sure to follow. Given the complexity of morphological and molecular subtypes in breast cancer, additional panels and combinations of panels will also likely be developed and validated.
Together, these predictive tools are poised to move the clinical management of breast cancer more squarely into the realm of personalized medicine, affording clinicians and patients a clearer picture of each patient’s treatment options and prognosis.
1. Alizart M, Saunus J, Cummings M, Lakhani SR. Molecular classification of breast carcinoma. Diagn Histopathol. 2012;18(3):97-103.
2. Furlow B. Special report: Cancer inquiry unveils Canada’s troubled health system. Lancet Oncol. 2008;9:823-824.
3. Glück S, de Snoo F, Peeters J, et al. Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat. 2013 (in press). Doi: 10.1007/s10549-013-2572-4
4. Drukker CA, Bueno-de-Mesquita JM, Retèl VP, et al. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. Int J Cancer. 2013 (in press). Doi: 10.1002/ijc.28082
5. Fumagalli D, Andre F, Piccart-Gebhart MJ, et al. Molecular biology in breast cancer: should molecular classifiers be assessed by conventional tools or by gene expression arrays? Crit Rev Oncol Hematol. 2012;84:e58-e69. Doi: 10.1016/j.critrevonc.2012.08.003