Clinical Topics

Gene Expression Signatures in Breast Cancer: A Surgical Oncologist’s Perspective

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Gene expression can serve to supplement the assessment of recurrence risk now used as the basis for chemotherapy or estrogen ablation recommendations for patients with breast cancer.


 

References

The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1

The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.

BREAST CANCER SUBTYPES

The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2

HER2 Type

The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.

Basal-like Tumors

The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1

HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.

Luminal Type (A and B)

The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.

It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9

GENE EXPRESSION SIGNATURE ASSAYS

One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11

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