Food for thought from ASCO 2022: breaking boundaries in breast cancer research

Published on 06/20/2022

11 min read

Last week we attended the 2022 American Society of Clinical Oncology (ASCO) meeting, gathering the world's leading researchers in oncology. Read our summary of four groundbreaking presentations on breast cancer research.

At ASCO 2022, oncology professionals gathered in Chicago, Illinois, and online to discuss the latest advances in research and care for patients with cancer. This year’s program featured over 200 sessions on Advancing Equitable Cancer Care Through Innovation. The presentations spanned from care delivery and regulatory policy to developmental therapeutics, gastrointestinal cancer, lung cancer, pediatric oncology, and beyond. Here, discover our summary of four outstanding ASCO presentations focusing on breast cancer treatment, diagnosis and follow-up, showcasing the power of precision medicine in healthcare.

Targetable genomic mutations in young women with advanced breast cancer1.

Norin Ansari, Yale New Haven Hospital, New Haven, CT

Advanced breast cancers (BC) in young women (under 40 years old) are often more aggressive and with worse prognoses than in older women. As treatment strategies can be dictated by the type of genomic alteration (GA), knowledge of BC genetic profiles across ages can greatly improve guidance and outcomes. In her poster presentation, Norin Ansari analyzed over 2,000 BC using hybrid-capture based comprehensive genomic profiling (CGP) to evaluate subtypes of GA and confirmed via immunohistochemistry (IHC) hormone receptors (HR) and PD-L1 status.

The study showed a mutations stratification within the population of BC depending on patient’s age. Indeed, younger patients had higher rates of BRCA1, BRCA2, and RB1 mutations and lower rates of CDH1 and PIK3CA mutations than did older patients. Differences were statistically significant in BRCA1, CDH1, and PIK3CA. Norin Ansari also showed that breast tumors in younger women were less likely to be estrogen receptor positive (ER+) and more likely to be triple negative while no clear age-related pattern for HER2 status could be highlighted. Finally, younger women were more often PD-L1 positive and had lower tumor mutational burden (TMB) than their older counterparts.

Different mutational profiles may support differential use of targeted and immune therapies.  

With increasing availability of targeted and immune therapies, knowing which GA each group of women has allows to better tailor therapies and leads to more effective treatments. For instance, BRCA1 mutations may lend to PARP inhibitor use while PIK3CA mutations may indicate the benefit of alpelisib prescription. The difference in genetic mutations between age groups can give a head start when treating women with breast cancer and CGP can refine the approach for better results.

Alpelisib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Biomarker analyses by next-generation sequencing from the SOLAR-1 study2.

Dejan Juric, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA

PIK3CA mutations account for approximately 40% of the hormone receptor positive (HR+), HER2-negative (HER2-) advanced BC. PIK3CA encodes for a subunit of PI3K, key of a highly interconnected pathway regulating growth and cell survival. PI3K pathway alterations are associated with endocrine therapy resistance, hence the poor prognosis for HR+, HER2– advanced BC.

Dejan Juric introduced the SOLAR-1 phase 3 study, a randomized controlled study testing the efficacy of the combined administration of alpelisib (ALP, a PI3Kα-selective inhibitor and degrader) and fulvestrant (FUL, a selective estrogen receptor degrader) in HR+, HER2- advanced BC patients. SOLAR-1 shows improved progression-free survival (PFS) in ALP + FUL treated patients versus placebo + FUL of 11.0 and 5.7 months, respectively. Going one step further, they measured the efficacy outcomes in patients with specific gene alterations (GA) in a PIK3CA-altered cohort, applying a retrospective exploratory biomarker analysis.

SOLAR-1 baseline tumor samples were tested by next-generation sequencing (NGS) and clinical benefit was assessed using PFS and hazard ratio based on TMB and GA status in the PIK3CA-altered cohort. While ALP + FUL clinical benefit was seen across TMB quartiles, it was more pronounced in patients with a low TMB (PFS of 18.5 months with ALP versus 3.2 months with placebo). They also observed that, despite improved PFS with ALP + FUL treatment in all PIK3CA-altered patients, the level of benefit may depend on the mutation status of other genes involved in MAPK pathway, PI3K pathway, in endocrine therapy or CDK4/6 inhibitors resistance. For instance, greater benefit was observed with altered FGFR1/2 but limited in MYC- and RAD21-altered cohorts. Besides, ALP + FUL efficacy was independent of GA in TP53, ESR1, CCND1, MAP3K1 and ARID1A.

Clinical benefit of ALP + FUL was maintained regardless of alterations in most biomarkers.

To conclude, Dejan Juric showed that ALP + FUL treatment was beneficial in patients with HR+, HER2– advanced BC, especially with a low TMB, but that a comprehensive understanding of the unique mutational profile of each tumor via biomarkers analysis may explain the level of success and thus dictate further care.

Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Results of DESTINY-Breast04, a randomized, phase 3 study3.

Shanu Modi, Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, NY, USA

Metastatic breast cancers (mBC) are classified according to the detection of certain receptors in the tumor cells, dictating the type of treatment to offer to the patients. Thus, mBC with an abnormally high quantity of human epidermal growth factor receptor-2 (HER2+) benefit from therapies targeting HER2 protein with monoclonal antibodies, while HER2- mBC receive treatment based on their HR status. However, the dichotomy between HER2+ and HER2- mBC does not suffice to find effective therapies for patients with low level of HER2 (HER2-low) currently treated as HER2-. The limited options and modest benefits of chemotherapy confirm the need for an adapted targeted strategy.

Trastuzumab deruxtecan (T-DXd) is part of a new generation of antibody-drug conjugates that delivers precision-focused chemotherapy directly to the cancer cells. Its activity was shown in tumors across a broad range of HER2 expression and a phase 1 trial showed promising efficacy of T-DXd in patients previously heavily treated with HER2-low mBC. Here, Shanu Modi presented us the DESTINY-Breast04 study, the first randomized phase 3 study of T-DXd for HER2-low mBC and its auspicious results.

Measuring the median progression-free survival (mPFS) in HR-positive mBC patients as primary endpoint, they observed statistically significant and clinically meaningful improvement for patients with HER2-low mBC compared to standard chemotherapy (mPFS 10.1 versus 5.4 months respectively: p<0.0001). Similar benefit was seen in all patients, regardless of their HR status, with T-DXd treatment through PFS and overall survival (OS) compared to standard chemotherapy.

DESTINY-Breast04 establishes HER2-low mBC as a targetable patient population with T-DXd as a new standard of care, with the potential to improve the survival for ~50% of all mBC patients.

We expanded the benefits of HER2 targeted therapy to a new population of breast cancer patients and established T-DXd as the new standard of care for HER2-low mBC.

These ground-breaking results presented at the 2022 ASCO Annual Meeting, and simultaneously published in the New England Journal of Medicine4, were acknowledged with a standing ovation from the audience of specialists. Anticipating these results to be practice changing, the study gives hope for many oncology professionals and patients.

Circulating tumor DNA and late recurrence in high-risk, hormone receptor–positive, HER2-negative breast cancer (CHiRP)5.

Marla Lipsyc-Sharf, Dana-Farber Cancer Institute, Boston, MA

Over half of metastatic recurrences in HR+ BC are late (occurring over 5 years from diagnosis) and thought to arise from minimal residual disease (MRD), a small number of cancer cells left in the body after treatment, hence the benefit of adjuvant therapy. MRD detection via circulating tumor DNA (ctDNA) is associated with high risk of BC recurrence in the early adjuvant setting across tumor subtypes. Little is known, however, about ctDNA for later settings.

Marla Lipsyc-Sharf presented the CHiRP prospective study of late recurrence in patients with high-risk HR+ BC without prior recurrence. 83 patients were followed with whole exome sequencing on primary tumor samples and plasma collection every 6-12 months to be processed with personalized RaDaRTM assay (12-51 variants) to detect ctDNA. Patients did not undergo routine surveillance body imaging or other circulating biomarkers testing. 68.7% of the patients had stage 3 disease and most received chemotherapy (90.4%) and adjuvant endocrine therapy (100%).

8 of 83 (10%) patients had detectable ctDNA at any timepoint during this study. As of last follow-up, 6 of them developed metastatic recurrence at various sites, 6-14 years after primary diagnosis, and one patient with detected ctDNA developed a locoregional recurrence.

All distant recurrences were detectable via ctDNA prior the recurrence with a median lead time of ~1 year.

Despite the low yet steady rate of recurrence in this small cohort with limited follow-up and infrequent plasma sampling (every 6-12 months), this study, published in Journal of Clinical Oncology6, shows that liquid biopsy can provide precious indication on the risk of relapse and thus point towards earlier intervention after MDR detection, improving patients’ survival and quality of life.

References

1 https://meetings.asco.org/abstracts-presentations/210258
2 https://meetings.asco.org/abstracts-presentations/209230
3 https://meetings.asco.org/abstracts-presentations/209021
4 Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer [published online ahead of print, 2022 Jun 5]. N Engl J Med. 2022;10.1056/NEJMoa2203690. doi:10.1056/NEJMoa2203690
5 https://meetings.asco.org/abstracts-presentations/209216
6 Lipsyc-Sharf M, de Bruin EC, Santos K, et al. Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer [published online ahead of print, 2022 Jun 4]. J Clin Oncol. 2022;JCO2200908. doi:10.1200/JCO.22.00908

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