Gene Profiling Essential Tool for Treatment Tailoring

Debu Tripathy, MD

Gene profiling assays can accurately and reproducibly assist decision making for patients with hormone receptor (HR)-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity, according to a presentation at the 37th Annual Miami Breast Cancer Conference^® by Debu Tripathy, MD.

“This is an area that touches all of the specialties of breast cancer treatment,” said Tripathy, professor and chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. “In the last 10 to 20 years, we’ve gotten more sophisticated tools, such as gene profiling, to further build out the subsets. We’re focusing on the benefits of chemotherapy, and there are many established prognostic factors that we all commonly use."

Table. Short- and Long-Term Effects of Treatment (Click to Enlarge)

National Comprehensive Cancer Network (NCCN) treatment recommendations provide guidance on the optimal test to utilized, based on the level of clinical evidence demonstrated in prospective validation, registry, population-based, and clinical trials. Based on findings from TAILORx and MINDACT trials, respectively, category 1 recommendations are given for Oncotype Dx for node-negative, HR-positive/HER2-negative disease and MammaPrint for node-negative to 1 to 3 node-positive breast cancer. Of these 2 tests, Oncotype DX is listed as preferred by the guideline and is the only to provide predictive value.¹

“There are many other assays that may be performed just as well but they aren’t tied to a randomized clinical trial,” Tripathy said.

TAILORx and Oncotype DX

The TAILORx trial² included more than 10,000 patients with HR-positive, HER2-negative, axillary node-negative breast cancer. Patients were stratified by risk using the Oncotype DX assay, with 9719 having follow-up information available for analysis. Overall, 69% (n = 6711) had an intermediate recurrence score of 11 to 25; 17% (n = 1619) had a score of 10 or lower; and, 14% (n = 1389) had a score of 26 or higher.

Those in the low-risk group received endocrine therapy alone while patients in the high-risk group were treated with the combination of chemotherapy and endocrine therapy. Patients in the intermediate group were randomized to receive either endocrine therapy alone (n = 3399) or chemotherapy plus endocrine therapy (n = 3312). Endocrine therapy most commonly consisted of an aromatase inhibitor for postmenopausal women and tamoxifen alone or with an aromatase inhibitor for premenopausal women.

After a median of 7.5 years of follow-up, endocrine therapy alone was noninferior to chemotherapy plus endocrine therapy for invasive disease-free survival (DFS) in the intermediate group (hazard ratio, 1.08; 95% CI, 0.94-1.24; P = .26). Moreover, freedom from recurrence at a distant site was similar between the two groups (hazard ratio, 1.10; 95% CI, 0.85-1.41; P = .48).

For those >50 years, there was no additional benefit observed with the addition of chemotherapy for patients with risk scores from 0 to 25. In those 50 years of age or younger, however, there was a benefit for adding chemotherapy in the intermediate risk group, although the rationale behind this is still unclear, Tripathy noted.

In this age group in those with a recurrence score of 16 to 20, there was a 1.6% different between for 9-year distant recurrence. In the 21 to 25 recurrence score group, 6.5% more patients recurred at 9 years in the endocrine alone arm compared with the chemotherapy plus endocrine arm (86.9% vs 93.4% freedom from recurrence rates).

“This might be explained by the fact that women in the younger age group can undergo menopause with chemotherapy, and it might be that benefit and not chemotherapy that is helping them,” said Tripathy. “This is still controversial to see whether we should be using chemotherapy or ovarian suppression instead. This is still a dilemma.”

MINDACT and MammaPrint

Findings from the MINDACT trial³ helped establish the 70-gene MammaPrint test as a tool for determining whether chemotherapy could be withheld. For this study, patients were stratified based on their clinical and genetic risk. Those with low risk by both measures (n = 2745) did not receive chemotherapy while those with high-risk for both were treated with chemotherapy (n = 1806). A second group with clinical-low but genetic-high (n = 592) risk or clinical-high but genetic-low (n = 1550) risk were randomized to receive chemotherapy or no chemotherapy.

In those with clinical-low/genetic-high risk, the 5-year distant metastasis-free survival (MFS) was similar regardless of treatment type, illustrating an ability to avoid chemotherapy. In the chemotherapy arm, the 5-year distant MFS rate was 95.8% compared with 95.0% in the chemotherapy-free arm (hazard ratio, 1.17; 95% CI, 0.59-2.28; P = .657). For those with clinical-high/genetic-low risk, the 5-year distant MFS was 95.9% in the chemotherapy group versus 94.4% in the chemotherapy-free arm (hazard ratio, 0.78; 95% CI, 0.50-1.21; P = .267).

“With this assay, you can really take the higher-risk group, primarily the node positive ones, and, if they have a low recurrence score, you might surmise that based on these data they may not benefit from chemotherapy,” said Tripathy. “This is what is reflected in the ASCO guidelines.”

The ASCO guidelines4 note that clinical utility for MammaPrint is only indicated in patients with high clinical risk, for both those with node-negative and node-positive cancers. ASCO also updated its guidelines, following the presentation of the TAILORx results. In these guidelines, chemotherapy is listed as having little to no benefit for those age >50 years with an Oncotype DX score of <26 or those with ≤50 years with a score of <16.

For the NCCN guidelines there are 5 gene tests listed for invasive breast cancer, specifically Oncotype DX, MammaPrint, Breast Cancer Index (BCI), Prosigna (PAM 50), and Endopredict.¹ Each of these assays examines different molecular characteristics and varying quantities of genes. The Oncotype DX test uses the expression of 21 genes, MammaPrint examines 70 genes, Prosigna is a 50 gene profile, BCI examines 7 key genes and ratios, and EndoPredict is a 12-gene panel. Additional assays continue to be assessed and will be added to the guidelines once they’re clinically validated, Tripathy noted.

References

1. Breast Cancer, version 2.2020. NCCN website. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 6, 202.
2. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018; 379:111-121.
3. Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016; 375:717-729.
4. Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update—integration of results from TAILORx. J Clin Oncol. 2019;37(22):1956-1964.

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Tailoring therapy can help avoid many of the short- and long-term side effects associated with various treatments (Table). The main prognostic criteria are tumor size, nodal status, tumor grade, and molecule profile, Tripathy noted. Several predictive factors also exist, which should be considered for each patient. In addition to HR status and HER2 expression levels, tumor grade and gene expression profiles can be used to determine the appropriateness of chemotherapy.