Multigene Assays Advance Genetic Testing in Breast Cancer, Drive Personalized Medicine

Link between genetics and breast cancer | Image Credit: David Carillet - stock.adobe.com

A review of multigene assays (MGAs) provided an overview of popular genetic tests that show promise for identifying therapeutics targets, allowing for patients with breast cancer to receive personalized cancer treatments leading to improved long-term outcomes and health care providers to better understand tumor biology.

Genetic testing, aided by tools like next-generation sequencing (NGS), is used for molecular typing, therapeutic targets, prognosis prediction, and assessing hereditary risk. This has facilitated patient subtyping based on hormone receptors, estrogen receptors, progesterone receptor, and HER2.

Assays analyzed genes linked to tumor biology (proliferation, invasion, immunity, inflammation) and internal control genes. Hereditary factors (5%-10% of cases) and mutations increase breast cancer risk, also affecting other organs, such as the thyroid, ovaries, prostate, bones, and gastrointestinal tract.

Genetic testing, alongside commercially available assays like Oncotype Dx, MammaPrint, RecurIndex, breast cancer index (BCI), EndoPredict, and Prediction Analysis of Microarray 50 (PAM50) inform prevention strategies for a significant portion (73.1%) of patients with stage I or II breast cancer.

Oncotype Dx, used widely in Europe and America, is also known as the 21-gene recurrence score (RS) assay. Initially, the risk of recurrence was categorized as low (RS < 18), intermediate (18 ≤ RS < 31), and high (RS ≥ 31). Chemotherapy benefits high-risk recurrence and offers little for low-risk recurrence, while the intermediate group remains unclear. No major differences in survival were observed between endocrine and chemoendocrine therapy for patients with an intermediate-risk of HR-positive breast cancer.

MammaPrint, a 70-gene signature predicting recurrence and metastasis for HR-positive, HER2- breast cancer in stage N0-N1. High and low-risk groups were created by testing 70 genes. Low-risk genomic and clinical patients avoided chemotherapy, while high-risk received it.

RecurIndex directs adjuvant therapy for N0, N1, andN2 stage patients with HR-positive breast cancer. This test analyzes 28 genes to assess the risk of distant metastasis in Asian patients while estimating the benefits of chemotherapy and radiotherapy. For patients with low-risk stage N1 breast cancer, RecurIndex found no statistical difference in local relapse-free survival (RFI), distant RFI, recurrence-free survival, and OS between those who received adjuvant radiotherapy and those who did not. However, high-risk patients saw significant improvements in these same measures with radiotherapy. RecurIndex can guide decisions about adjuvant radiotherapy, recommending it for patients with high-risk stage N1 to reduce recurrence risk.

The postmenopausal HR-positive, node-negative patients with breast cancer were developed by BCI to predict prognosis and the endocrine therapy responses while analyzing 11 genes (5 related to progression and HOXB13 and IL17BRratio). After 10 years, high-risk patients on tamoxifen benefited from extended therapy due to higher recurrence risk, while low-risk patients did not. Scores correlated with distant recurrence-free rate in both node-positive and node-negative groups. Additionally, EndoPredict showed a 4.8% increase in high-EPclin score patients receiving chemotherapy, supporting its predictive value in adjuvant chemotherapy benefit.

The PAM50 assay, analyzing 55 genes, classifies breast cancer into luminal A, luminal B, HER2–enriched, and basal-like subtypes that guide treatments for HR-positive, HER2-negative, and stage N0 or N1 patients, regardless of other molecular subtypes.

Genetic testing is significant to the basis and prerequisite for precision medicine following the comprehension of biomarkers. Main biomarkers include phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), estrogen receptor 1 (ESR1), CDK 4/6, BRCA 1/2, markers for immunotherapy or antibody-drug-conjugates, circulating tumor DNA (ctDNA), and circulating tumor cells (CTC).

Genetic testing in metastatic breast cancer aids treatment selection. Patients with HER2-positive breast cancer benefit from targeted therapies, including trastuzumab and pertuzumab, prompting exploration of mutations driving drug resistance. Combining drugs like alpelisib and ado-trastuzumab shows promise in patients with trastuzumab-resistant HER2-positive advanced breast cancer with an objective response rate higher than that of ado-trastuzumab alone.

In metastatic triple-negative breast cancer (TNBC), genetic testing holds promise with ctDNA, a non-invasive liquid biopsy, accurately monitors treatment response, unlike CTCs. Mutations like HER2 and AKT1 detected in ctDNA guided effective therapies, highlighting the potential of ctDNA testing in personalized medicine. However, further research is needed to explore the full potential of this approach.

Genetic testing unlocks personalized medicine for breast cancer subtypes such as HR-positive, HER-2-positive, and TNBC, enabling better stratification, targeted therapy, and hereditary risk assessments.

Study limitations include potential ethnic bias due to Western-derived databases and controversial clinical utility, hindering their promotion despite confirmed reliability and high cost.

Breast cancer treatment should prioritize molecular subtypes and clinical stages. Genetic testing, revealing oncogenic driver mutations and gene expression, benefits patients in all stages, enabling targeted therapies like immunotherapy and ADCs. This paves the way for accessible and cost-effective genetic testing, leading to precise and personalized breast cancer management.

Reference

Yang T, Li W, Huang T, Zhou J. Genetic testing enhances the precision diagnosis and treatment of breast cancer. Int J Mol Sci. 2023; 24(23):16607. doi:10.3390/ijms242316607