Can We Use Genomic Profiling Data to Influence Locoregional Treatment Decisions in Breast Cancer?

Terry P. Mamounas, MD, MPH; Melissa P. Mitchell, MD, PhD; and Wendy A. Woodward, MD, PhD
Published: Thursday, Mar 05, 2020

Terry P. Mamounas, MD, MPH

Terry P. Mamounas, MD, MPH

In early-stage breast cancer, molecular subtyping and gene expression profiling has improved our ability to estimate risk of distant recurrence above and beyond traditional clinicopathologic factors and biomarkers.1-7 Despite this considerable progress in refining risk of distant recurrence, risk assessment for locoregional recurrence (LRR) is still primarily based on traditional clinicopathologic factors such as patient age, tumor size, grade, pathologic nodal status, presence of lymphovascular space invasion, and margin width.8,9 In addition, several studies have shown that tumor subtype alone is strongly predictive of LRR.5,10-16 Given the solid correlation between the risk of LRR and distant recurrence,17-19 several investigators have examined whether genomic assays that predict risk of distant recurrence can also predict risk of LRR.20-28 Increasingly, new genomic classifiers are being developed specific to LRR, in patients with node-negative and node-positive invasive breast cancer.29,30 There is also increasing interest in developing gene expression assays to predict response to radiation therapy (XRT).30-39

Can Genomic Profiling Affect the Surgical Management in the Breast or Axilla?

Local recurrence is also strongly infl uenced by the surgical approach. To date, molecular subtyping/ genomic profi ling has very little to no infl uence on the extent of surgical therapy, which is traditionally based on the anatomic extent of the tumor and not on underlying tumor biology. Anatomic extent of the tumor in the breast and axilla can be reduced by neoadjuvant therapy, which results in tailoring of the surgical approach. However, in the traditional model of surgery fi rst followed by adjuvant systemic therapy, genomic profi ling has very little infl uence on the extent of surgical therapy.

Can Genomic Profiling Affect the Use of Adjuvant XRT?

By individualizing risk of LRR with molecular subtyping and use of genomic classifi ers, it is hoped that use of adjuvant XRT can also be tailored. Currently, there are 2 approaches for tailoring use of XRT. First, is the potential of customizing the use of postmastectomy and regional nodal XRT. Second, is the potential of avoiding breast XRT in selected candidates at low risk of in-breast recurrence after breast-conserving surgery (BCS).

Adjuvant Postmastectomy and Regional Nodal Radiation Therapy

The association between the 21-gene recurrence score (RS) and risk of LRR has been evaluated in patients with node-negative, estrogen receptor (ER)–positive breast cancer treated with either no adjuvant therapy, tamoxifen, or tamoxifen plus adjuvant chemotherapy as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and NSABP B-20 trials.40 Patients treated with BCS received breast XRT but patients who underwent a mastectomy received no XRT. RS was a significant predictor of LRR in all 3 groups of patients.

In 895 patients treated with tamoxifen, the 10-year estimates of the proportion of patients with LRR were 4.3%, 7.2%, and 15.8% for patients with low, intermediate and high RS, respectively (P <.001). Similar association between RS and risk of LRR was identified in 424 patients treated with chemotherapy plus tamoxifen in the B-20 trial (10-year LRR rates: 1.6%, 2.7%, and 7.8% for patients with low, intermediate, and high RS, respectively [P = .028]). This 5-fold diff erence in LRR between low versus high RS in patients treated with chemo-endocrine therapy is biologically interesting but has limited clinical implications for patients with node-negative disease relative to the potential need (or benefi t from) postmastectomy or regional nodal XRT.

The previously mentioned observations of low LRR risk in patients with a low RS (<18) were recently confirmed in a large, contemporary cohort of patients with node-negative, ER-positive/HER2-negative breast cancer from Memorial Sloan Kettering Cancer Center.26 Most patients were treated with BCS plus XRT (66.6%) or total mastectomy alone (29.7%), endocrine therapy alone (84.8%), or chemo-endocrine therapy (12.1%). With a median follow-up of 52 months, the LRR rate was 0.9% overall and 0.7% in patients treated with adjuvant endocrine therapy only.

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