The Importance of Testing for PIK3CA

  • Among women with hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer, approximately 40% harbor mutations in the PIK3CA gene, which plays a crucial role in tumor growth and progression by activating the PI3K/AKT/mTOR signaling pathway​.
  • Testing for PIK3CA mutations is essential for these patients, as it identifies candidates for targeted therapies like alpelisib and inavolisib.

Breast cancer remains a leading cause of cancer-related mortality among women, with hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer being the most common subtype. Among these, approximately 40% of patients harbor mutations in the PIK3CA gene, which plays a crucial role in tumor growth and progression by activating the PI3K/AKT/mTOR signaling pathway​. Identifying these mutations is critical for guiding targeted therapies, particularly with PI3K inhibitors such as alpelisib (brand name PiqRay)  and inavolisib (not yet FDA approved). 

Although these treatments come with side effects, they represent a critical advancement in breast cancer therapy, particularly for patients who have developed resistance to traditional endocrine therapies.

The Importance of Genetic Testing for PIK3CA Mutations

Testing for PIK3CA mutations is essential in patients with advanced HR+/HER2− breast cancer, as it identifies candidates for targeted therapies like alpelisib and inavolisib. Genetic testing can be performed on both tumor tissue and plasma using circulating tumor DNA (ctDNA).

Studies show a strong correlation between tissue and plasma testing methods, although tissue remains the gold standard.

“PIK3CA mutation is there at the diagnostic biopsy. It’s not acquired under the pressure of hormone therapy. So you can test for that at any time. But now that we’re doing liquid biopsies on progression after first-line therapy, that’s typically when I’m starting to look for these genomic alterations,” Dr Heather MacArthur, Director of Breast Cancer at UT Southwestern in Dallas, Texas, tells SurvivorNet Connect.

PIK3CA mutations most frequently occur in exon 9 (E542K and E545K) and exon 20 (H1047R). Detection of these mutations is associated with poorer prognosis and greater resistance to endocrine therapies making the identification of these mutations critical in treatment planning.

PI3K Inhibitors in Treatment: Alpelisib

PiqRay is a highly selective inhibitor of the alpha isoform of PI3K (PI3Kα), specifically targeting the PIK3CA mutation. The SOLAR-1 trial demonstrated the efficacy of alpelisib in combination with fulvestrant in patients with PIK3CA-mutated, HR+/HER2− breast cancer.

SOLAR-1 Study Design

The SOLAR-1 trial was a phase 3, randomized, double-blind study that evaluated alpelisib in combination with fulvestrant in postmenopausal women and men with PIK3CA-mutated, HR+, HER2-negative ABC. Patients were randomized to receive either alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Importantly, all patients had previously progressed on or after treatment with an aromatase inhibitor (AI), and no prior chemotherapy for advanced disease was allowed.

Efficacy Results

The final overall survival (OS) analysis showed a numeric improvement of 7.9 months in median OS for patients receiving alpelisib plus fulvestrant (39.3 months vs. 31.4 months; HR 0.86, 95% CI 0.64-1.15). Although this improvement did not meet the prespecified threshold for statistical significance, it supports the clinical benefit of alpelisib in this population.

Subgroup analyses revealed that patients with lung or liver metastases had a more pronounced OS benefit, with a median OS of 37.2 months for alpelisib versus 22.8 months for placebo (HR 0.68, 95% CI 0.46-1.00).

Safety Profile

The safety profile of alpelisib was consistent with its known mechanism of action, with the most common adverse events (AEs) including hyperglycemia (64.8% of patients), diarrhea (59.5%), nausea (46.8%), and rash (36.3%). Grade 3 or higher AEs were more frequent in the alpelisib group, particularly for hyperglycemia (33.1%), diarrhea (7.0%), and rash (9.9%). These side effects were generally manageable with dose adjustments, concomitant medications, and close monitoring​.

Notably, the incidence of hyperglycemia, a known side effect of PI3K inhibition, was significantly higher in the alpelisib group (64.8% vs. 9.4% in the placebo group). Patients who experienced this AE were managed with antidiabetic medications such as metformin, and in most cases, hyperglycemia was reversible.

Inavolisib as an Emerging Therapy

Inavolisib is a newer PI3Kα-specific inhibitor currently being evaluated in clinical trials. The INAVO120 Phase III trial evaluated inavolisib in combination with palbociclib and fulvestrant for patients with PIK3CA-mutated, HR+/HER2− breast cancer. This combination significantly improved progression-free survival and delayed the need for chemotherapy.

“At San Antonio last year, there was the data from the INAVO120 study looking at triplet therapy in patients with PIK3CA mutations as first-line therapy with incredibly promising data. So further updates from that study are anticipated as is an FDA approval for first line,” Dr. MacArthur explains.

Study Design and Primary Results

The INAVO120 trial enrolled 325 patients with PIK3CA-mutated, HR+, HER2-negative LA/mBC, all of whom had relapsed either during or within 12 months of completing adjuvant endocrine therapy. The patients were randomized to receive either inavolisib combined with palbociclib and fulvestrant (Inavo+Palbo+Fulv) or placebo with palbociclib and fulvestrant (Pbo+Palbo+Fulv).

The primary endpoint of progression-free survival (PFS) was met, with the inavolisib combination achieving a median PFS of 15 months compared to 7.3 months in the placebo arm (hazard ratio: 0.43, 95% confidence interval [CI]: 0.32-0.59). This represents a significant improvement in disease control for patients receiving inavolisib.

While there was a trend toward improved overall survival (OS), the data were not mature enough to reach statistical significance. The median OS in the inavolisib group was not yet estimable, while the placebo group had a median OS of 31 months (stratified HR 0.64, 95% C I 0.43-0.97).

Safety and Adverse Events

The safety profile of inavolisib was manageable, though it included a few notable grade ≥3 adverse events. These included neutropenia (80% with inavolisib versus 78% with placebo), thrombocytopenia (14% versus 4.3%), leukopenia (6.8% versus 11%), and anemia (6.2% versus 1.9%). Inavolisib-specific grade ≥3 adverse events that were not observed in the placebo group included hyperglycemia (5.6%), diarrhea (3.7%), and stomatitis or mucosal inflammation (5.6%). While these events were manageable and often reversible, they highlight the need for close monitoring in clinical practice.

Clinical Implications

The findings from the INAVO120 trial underscore the potential of inavolisib as part of a combination therapy for PIK3CA-mutated, HR+, HER2-negative LA/mBC patients who have become resistant to endocrine therapy. The combination with palbociclib and fulvestrant provides a new therapeutic strategy, significantly extending progression-free survival. Moreover, inavolisib delayed the need for subsequent therapies, including chemotherapy, by nearly nine months.

However, it is important to note that inavolisib is not yet approved for any indication. Further follow-up and additional trials will be necessary to fully understand its long-term benefits, particularly with regard to overall survival.