Finding Actionable Biomarkers Like ESR1 and PIK3CA in Metastatic Breast Cancer to Drive Precision Medicine

The challenge of precision medicine in metastatic breast cancer is to develop well-tolerated therapies based on key actionable, accessible, and validated biomarkers, said Francisco J. Esteva, MD, PhD, during an explanation of the current understanding of the molecular landscape of metastatic breast cancer at the <em>16th Annual </em>International Congress on the Future of Breast Cancer East.

Francisco J. Esteva, MD, PhD

The challenge of precision medicine in metastatic breast cancer is to develop well-tolerated therapies based on key actionable, accessible, and validated biomarkers, said Francisco J. Esteva, MD, PhD, during an explanation of the current understanding of the molecular landscape of metastatic breast cancer at the16th AnnualInternational Congress on the Future of Breast Cancer East, hosted by the Physicians’ Education Resource®, LLC (PER®). While several biomarkers have been identified in patients with breast cancer, includingESR1andPIK3CAmutations, not all of these are driver mutations that can be effectively targeted with treatment.

“We need to find the biomarkers that have a possibility to respond to treatment, monitor response, or understand treatment resistance,” said Esteva, professor of medicine, associate director of clinical investigation, and director of the Breast Medical Oncology Program, Laura and Isaac Perlmutter Cancer Center, New York University Langone Cancer.

Currently, the essential biomarkers in the treatment of patients with breast cancer are the estrogen receptor, progesterone receptor, HER2, and activatingBRCAmutations, which he noted are especially important to identity in the use of PARP inhibitors.

Clinical trials have also identified promising biomarkers inAKT1, PIK3CA, PTEN, ESR1,FGFR1 amplification, and more. However, there is difficulty in proving their clinical utility. “Once we find a mutation, it is not always a driver mutation,” he said.

There is a great deal of variety in the number of mutations seen in primary breast cancer tumors, Esteva noted. In an analysis of common mutations in patients with primary breast cancer according to breast cancer subtype using next-generation sequencing, the Cancer Genome Atlas Network found that somatic non-silentPIK3CAmutations were commonly seen in luminal tumors, specifically the luminal A subtype (45%), which had the highest degree of significantly mutated genes, the luminal B subtype (29%), and in HER2-enriched tumors (39%).1TP53mutations were seen in 37% of cases, including 80% in basal-like tumors. Only 30% of cases showed a single driver mutation alone.

Only a handful of frequent mutations were noted in metastatic breast cancer tumors compared with early breast cancer tumors:ESR1, FSIP2, AGRN, FRAS1, IGFN1, EDC4, OSBPL3,andPALB2.2TheESR1mutation was noted in approximately 30% of the metastatic breast cancer tumors, Esteva pointed out. The researchers determinedESR1to be a driver mutation as well as a metastatic gene.

Lefebvre et al also found that patients with metastatic breast cancer and a somatic mutation in 1 of the 8 genes had a worse prognosis. Patients without driver mutations had a longer overall survival than those with driver mutations.

Across 4 studies involving endocrine therapy in patients with hormone receptor (HR)—positive advanced or metastatic breast cancer,ESR1mutations were found in approximately 30% of patients.3In the FERGI trial, 37.3% of patients harbored anESR1mutation, 39.1% in the SOFEA trial, 25.3% in the PALOMA-3 trial, and 28.8% in the BOLERO-2 trial.

ESR1mutations are prognostic and predictive biomarkers of resistance to aromatase inhibitors in patients with metastatic disease, as was seen in these 4 trials, but they can also be helpful in guiding treatment of endocrine-based therapies.

In the SOFEA trial, patients withESR1mutations, which were discovered retrospectively using circulating tumor DNA (ctDNA) from archival plasma samples, demonstrated improved progression-free survival (PFS) rates with fulvestrant (Faslodex) when compared with exemestane (Aromasin) (HR, 0.52; 95% CI, 0.30-0.92;P= .02), whereas those with wild-typeESR1had similar PFS rates with either treatment (HR, 1.07; 95% CI, 0.68-1.67;P= .77).4

And in the PALOMA-3 trial, the addition of palbociclib (Ibrance) to fulvestrant improved PFS over fulvestrant alone among patients with bothESR1-mutant (HR, 0.43; 95% CI, 0.25 to 0.74;P= .002) andESR1wild-type (HR, 0.49; 95% CI, 0.35 to 0.70;P<.001).

Buparlisib, a pan-PI3K inhibitor, was investigated in combination with fulvestrant in the phase III BELLE-3 trial in comparison with fulvestrant alone in patients with HR-positive locally advanced or metastatic breast cancer following progression on or after an mTOR inhibitor.5Esteva said that the addition of buparlisib led to a small improvement with a PFS rate of 3.9 versus 1.8 months for placebo plus fulvestrant, representing a 33% reduction in the risk of progression or death (HR, 0.67; 95% CI, 0.53-0.84;P<.001).

Upon tissue testing in 321 patients,PIK3CA-mutated tumors were found in 34%. Among these patients, the median PFS with the buparlisib combination was 4.7 versus 1.4 months with fulvestrant alone (HR, 0.39; 95% CI, 0.23-0.65;P<.001). Limited benefit was seen for those withPIK3CAwild-type tumor, with a median PFS of 2.8 versus 2.7 months, for buparlisib and placebo, respectively (HR, 0.83; 95% CI, 0.60-1.14;P= .117).

Patients withPIK3CA-positive tumors according to ctDNA analysis (n = 348; 39%), the median PFS with buparlisib was 4.2 months versus 1.6 months with fulvestrant plus placebo (HR, 0.46; 95% CI, 0.29-0.73;P<.001). In the wild-type group, the PFS with the PI3K inhibitor was 3.9 versus 2.7 months with placebo (HR, 0.73; 95% CI, 0.53-1.00;P= .026).

However, a greater toxicity profile was noticed with the combination. Instead, Esteva suggested moving toward the higher specificity and bioactivity seen with the more tolerable PI3K-alpha inhibitors.

“If [the benefit of PI3K inhibitors in patients withPIK3CAmutations] is confirmed, particularly with the more tolerable PI3K-alpha selective inhibitors, this may be an area of research to select these patients,” he said.

Going forward, to improve upon the discovery of biomarkers to aid in guiding precision medicine for patients with breast cancer, Esteva suggested looking to pathway activation and dependency, multiple genomic alterations, and functional studies to find more actionable and accessible biomarkers.


  1. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors.Nature. 2012;490:61-70. doi: 10.1038/nature11412.
  2. Lefebvre C, Bachelot T, Filleron T, et al. Mutational profile of metastatic breast cancers: a retrospective analysis.PLoS Med. 2016;13(12):e1002201. doi: 10.1371/journal.pmed.1002201.
  3. Jeselsohn R, De Angelis C, Brown M, Schiff R. The evolving role of the estrogen receptor mutations in endocrine therapy-resistant breast cancer.Curr Oncol Rep. 2017;19(5):35. doi: 10.1007/s11912-017-0591-8.
  4. Fribbens C, O&rsquo;Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer.J Clin Oncol.2016;34(25):2961-2968. doi: 10.1200/JCO.2016.67.3061.
  5. Di Leo A, Keun SL, Ciruelos E, et al. BELLE-3: A Phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S4-07.