In order to facilitate the implementation of precision medicine in the clinical management of cancer, harmonizing and standardizing reporting and interpretation of clinically relevant genomics data is key. To accomplish this, a team of leading cancer specialists in Europe and North America developed a scale, called ESCAT (ESMO Scale for Clinical Actionability of molecular Targets).

The ESCAT scale, which ranks the likelihood of genomic alterations to serve as therapeutic targets based on the strength of evidence from clinical studies, focuses on the clinical evidence for matching tumor mutations with therapies available in the clinic and is designed to give a common vocabulary for communication between clinicians, and for explaining potential treatment benefits to patients. In this way, the scale optimizes patient care by making it easier to identify patients with cancer who are likely to respond to precision medicines and help make treatment more cost-effective. [1]

While multiple studies have shown feasibility and demonstrated preliminary evidence of utility, evidence was still showing how multigene sequencing could improve outcomes in patients diagnosed with metastatic breast cancer was still lacking. The SAFIR02-BREAST trial –  funded by Fondation ARC, Breast Cancer Research Foundation, Agence Nationale de la Recherche (IHU-B) –  was designed to assess if there was a clinical use and possible benefit. And results from the SAFIR02-BREAST trial, presented at the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021, indeed demonstrated that ESCAT was highly predictive of the benefits of targeted therapies matched to genomic alterations.

As part of the study, scientists observed that the use of multigene sequencing as a therapeutic decision tool improved the outcomes for patients with metastatic breast cancer when the genomic alterations identified were ranked in the I/II tiers of the ESMO Scale.

“[Today, Oncologists] receive a growing amount of information about the genetic make-up of each patient’s cancer, but this can be difficult to interpret for making optimal treatment choices,” said Professor Fabrice André, MD, Ph.D., the research director at Gustave Roussy Cancer Campus and a committee member of Chair of the ESMO Translational Research and Precision Medicine Working Group.

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Multigene sequencing
Next-generation genome analysis (NGS) technologies offer massively parallel sequencing that offers ultra-high throughput, scalability, and speed. Using this technology allows researchers to simultaneously sequence multiple genes and to establish the mutational profile of a patient’s tumors. This can help with targeting the identified alterations with therapeutics that may not be the standard of care for that disease, with the goal of improving patient outcomes.

“Multigene sequencing has been widely implemented but its clinical impact and the best framework for its use remain unclear,” André explained.

“The main purpose of the SAFIR02-BREAST trial was to test whether genomic analyses are useful for patients with metastatic breast cancer, and how we can best analyze the results.”

Study design
The phase II SAFIR02-BREAST trial enrolled a total of 649 patients with metastatic, HER2-negative breast cancer to evaluate whether targeted therapies guided by genomics improve progression-free survival (PFS) compared to maintenance chemotherapy. Patients who had received more than two lines of chemotherapy or one of the targeted therapies evaluated in the trial were not eligible to participate.[2]

Patients with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by next-generation sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was evaluated by whole-exome sequencing (n = 617) and the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n = 44) by next-generation sequencing and digital PCR.

The researchers performed a pooled analysis of this trial and the SAFIR-PI3K trial that compared a combination of the PI3Kα-specific inhibitor alpelisib (Piqray®; Novartis) and the estrogen receptor antagonist fulvestrant (Faslodex®; AstraZeneca) with maintenance chemotherapy in patients with PIK3CA-mutated metastatic breast cancer.

Genomic analysis through next-generation sequencing and SNP array was performed on 1,462 patients. The investigators assigned 238 patients whose disease was stable after six to eight cycles of chemotherapy and who carried known genomic alterations to either the appropriate targeted therapies matched to their genomic alteration (157) or maintenance chemotherapy (81).

The study investigated drugs including vistusertib (AZD2014), an mTOR inhibitor with IC50 of 2.8 nM in a cell-free assay and highly selective against multiple PI3K isoforms (α/β/γ/δ); AZD4547, a potent, specific, orally bioavailable fibroblast growth factors receptor (FGFR) tyrosine kinase inhibitor; capivasertib, an oral AKT inhibitor, sapitinib, an erbB receptor tyrosine kinase inhibitor, selumetinib (Koselugo®; AstraZeneca), vandetanib (Caprelsa®; Genzyme Corporation), bicalutamide (Casodex®; AstraZeneca), olaparib (Lynparza®; AstraZeneca), and alpelisib.  These agents were matched to specific targets including m-TOR, EGFR, AKT, HER2 or EGFR, MEK, VEGF or EGFR, androgen receptor, and PARP. Genomic alterations in the patients’ tumors were classified using the ESCAT scale.

Study results
In 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 and 2.8monthsinthematched targeted therapy and maintenance chemotherapy arms, respectively. On the contrary, there was no significant difference in PFS between the two arms in the overall population, and targeted therapies were not effective when matched to alterations that did not rank as ESCAT I/II, suggesting that the ESCAT classification was highly predictive of the benefits of targeted therapies matched to genomic alterations.

“[The results of this study] showed that genomic analysis improves the outcome of patients with metastatic breast cancer if they carry alterations classified as ESCAT I/II,” André explained.

“These findings suggest that genomics should be a part of the pathway of care, but it has no impact if the results are not interpreted using a validated framework of actionability of the gene alterations identified.”

In addition to testing for known genetic alterations, multigene sequencing also allows researchers to discover new ones. André and colleagues identified 21 gene amplifications or deletions associated with metastatic evolution, poor prognosis, and drug resistance or sensitivity.

“The general implication of [the] study is that precision medicine can improve patient outcome if it is interpreted with the right tools,” André concluded.

According to the researchers, the main limitation of this study is the limited number of targeted therapies matched to the genomic alterations found.

Clinical trials
SAFIR02_Breast – Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (SAFIR02_Breast) – NCT02299999
SAFIR-PI3K A Phase II Randomized Maintenance Trial Comparing Alpelisib and Fulvestrant Versus Chemotherapy in PIK3CA Mutated Advanced Breast Cancer (SAFIR-PI3K) – NCT03386162

Highlights of prescribing information
Alpelisib (Piqray®; Novartis) [Prescribing Information]
Selumetinib (Koselugo®; AstraZeneca) [Prescribing Information]
Vandetanib (Caprelsa®; Genzyme Corporation) [Prescribing Information]
Bicalutamide (Casodex®; AstraZeneca) [Prescribing Information]
Olaparib (Lynparza®; AstraZeneca) [Prescribing Information]

Meeting Abstract
Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST, presented during the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021

[1] Mateo J, Chakravarty D, Dienstmann R, Jezdic S, Gonzalez-Perez A, Lopez-Bigas N, Ng CKY, Bedard PL, Tortora G, Douillard JY, Van Allen EM, Schultz N, Swanton C, André F, Pusztai L. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2018 Sep 1;29(9):1895-1902. doi: 10.1093/annonc/mdy263. PMID: 30137196; PMCID: PMC6158764.
[2] Mosele F, Stefanovska B, Lusque A, Tran Dien A, Garberis I, Droin N, Le Tourneau C, Sablin MP, Lacroix L, Enrico D, Miran I, Jovelet C, Bièche I, Soria JC, Bertucci F, Bonnefoi H, Campone M, Dalenc F, Bachelot T, Jacquet A, Jimenez M, André F. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2020 Mar;31(3):377-386. doi: 10.1016/j.annonc.2019.11.006. Epub 2020 Jan 24. PMID: 32067679.

Featured image: SABCS 2019 San Antonio Breast Cancer Symposium – Speakers and attendees during the morning sessions held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo Courtesy: © 2019 SABCS/AACR Todd Buchanan. Used with permission.

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