Case description:
A 65 year-old woman was diagnosed with a metastatic breast cancer, hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Thanks to our OncoDEEP analysis, we notably detected a variant PIK3CA p.H1047R and a variant ESR1 p.D538G.
Clinical interpretation:
We found a PIK3CA p.H1047R variant, which is one of the most common PIK3CA variant in breast cancer patients (PMID:36279023, PMID:32637176). This variant may lead to increased activation of the PI3K/Akt/mTOR pathway which mediates different processes like promoting cell transformation, tumour initiation and proliferation, and resistance to apoptosis. Results from SAFIR02 reported that PIK3CA-mutated HR+/HER2- mBC patients present a poor outcome and resistance to chemotherapy (PMID: 32067679), In such case, PI3K inhibitors would show potential clinical benefit for this patient.
In 2019, FDA approved the PI3K inhibitor alpelisib in combination with fulvestrant for postmenopausal women, and men, with HR+/HER2-, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha PIK3CA-mutated, advanced or metastatic breast cancer. Indeed, in the phrase 3 study SOLAR-1 (NCT02437318), an increase of the progression-free survival (PFS) was found in patients treated with alpelisib plus fulvestrant as compared to placebo sub-group. In addition, several clinical trials are recruiting patients to test other PI3K inhibitors.
We also detected an ESR1 p.D538G variant. It is associated in vitro with a constitutive activity and in vivo with resistance to anti-estrogen therapies (PMID: 24185510; PMID: 24185512; PMID: 24055055). This variant has been associated with a worse prognosis and is one of the most frequent mutations in breast cancer associated with a progression through aromatase inhibitor therapy (PMID: 27269946; PMID: 28361033). Interestingly, ESR1 mutations were found in ~40% of patients that progressed on aromatase inhibitors therapy and are numerically enriched in luminal A and PIK3CA-mutated tumours (PMID: 27174596). Based on such information, this patient should not be sensitive to aromatase inhibitors (i.e. Anastrozole, Letrozole, Exemestane). Similarly, the detection of this ESR1 variant (p.D538G) could reduce the efficacy of ER antagonists such as Tamoxifen citrate. (PMID : 24185512 ; PMID : 24185510) Nonetheless, It has also been reported that the PFS is increased from 2.6 months for patients who received exemestane to 5.7 months for those given fulvestrant. Fulvestrant can thus still be recommended for this patient. In addition, several clinical trials are recruiting patients to test other anti-estrogen alone or in combination with CDK4/6 inhibitors,
Finally, others variants have been detected (i.e. NFN stop and BRCA loss of heterozygosity). No therapy is approved in breast cancers with those variants but clinical trials are recruiting.
