PIK3CA mutation + HR positive

BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

No abstract available

At current drug prices, alpelisib plus fulvestrant is not cost effective for patients with PIK3CA-mutated, HR+/HER2- ABC from a US payer perspective. Given the considerable progression-free survival (PFS) and overall survival (OS) benefits observed with alpelisib in this setting, further discussion and negotiation of the price of alpelisib are warranted to provide more favorable economic outcomes and thereby increase the value of the alpelisib plus fulvestrant regimen in patients.

The sonographic features of PIK3CA-mutated breast cancers were strongly associated with extensive and liquefied necrosis. The ability to predict molecular subtypes, particularly using US to detect the triple-negative subtype, may play an important role in early management and treatment.

Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer.

PIK3CA status is most often assessed in this group of pts and combination of alpelisib - PIK3CA inhibitor and fulvestrant is second-line treatment option in PIK3CA mutated pts. There was no relevant difference in TTF between two groups. However, PIK3CA mutated subgroup had more aggressive clinical features - more often presented with bone marrow infiltration and de novo aBC, statistically relevant OR 5.158 and 2.323 respectively, which is related to lower quality of life and highlights the importance of treatment improvement for this subgroup of pts. >*Statistically significant p<0.05.

Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, is indicated in combination with fulvestrant (FUL) for pts with HR+, HER2− ABC following progression on/after endocrine therapy (ET)-based treatments (tx)... Cohort A (ALP + FUL) comprised 127 pts whose immediate prior tx was CDK4/6i + aromatase inhibitor (AI); Cohort B (ALP + letrozole) enrolled 126 pts whose immediate prior tx was CDK4/6i + FUL... After ≥18 mo follow-up, with mature data, ALP + ET demonstrated clinical activity in BYLieve Cohorts A, B, and C. Within the trial, ALP + ET showed median OS between 20.7 mo and 29.0 mo following prior CDK4/6i, chemotherapy, or ET. AEs associated with ALP were well defined and manageable, with no new safety signals observed in any cohort. Clinical trial information: NCT03056755.

While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.

Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.

Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, is indicated in combination with fulvestrant (FUL) for pts with PIK3CA-mutated (mut) HR+, HER2− ABC following progression on/after ET- based treatments...Here we report the results of a biomarker analysis using paired baseline (Cycle 1 Day 1) and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples from pts in BYLieve Cohorts A and B. In the BYLieve study, pts with PIK3CA-mut, HR+, HER2− ABC had CDK4/6i + aromatase inhibitor (Cohort A; N=127) or CDK4/6i + FUL (Cohort B; N=126) as treatment immediately prior to receiving ALP + FUL and ALP + letrozole, respectively... Between baseline and EOT, only small variations in gene alterations in PIK3CA- mutated HR+, HER2– ABC were observed in the post-CDK4/6i setting. As the disease progressed, increases in loss-of-function mutations in PTEN at EOT in both Cohorts A and B suggested loss of PTEN in PI3K pathway may drive resistance to ALP. Early intervention with ALP, when the tumor is particularly driven by PIK3CA oncogenic mutations and before it develops more genomic complexity, may potentially provide better clinical outcomes.

Background: ALP is a PI3Kα inhibitor and degrader approved with fulvestrant for the treatment (tx) of patients (pts) with PIK3CA-mutated, HR+, HER2– ABC... Per the HG panel, (a) ALP tx is appropriate in individuals with HbA1c 6.5% to < 8% with a pre-tx endocrinology consult; (b) low carbohydrate diet is appropriate in all pts starting ALP; (c) prophylactic metformin is appropriate in pts with baseline HbA1c 5.7%-6.4%; may also be appropriate in pts with HbA1c < 5.7%; (d) after metformin, an SGLT2 inhibitor or a thiazolidinedione is an appropriate second-/third-line anti-HG agent (or first-line in metformin-intolerant pts), while insulin is not. Until further evidence is available, these expert recommendations provide guidance on prevention and management of HG and rash related to ALP tx in routine clinical practice.

We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented.

We have demonstrated the feasibility of a comprehensive liquid biopsy for simultaneous monitoring of PI3K pathway mutations in ctDNA and PI3K pathway signaling in CTCs via transcriptional profiling and phospho-protein expression in patients with MBC. Future work will prospectively evaluate this assay in patients receiving alpelisib for PIK3CA-mutated MBC. This has the potential to complement PIK3CA mutation status as a biomarker of sensitivity to PI3K therapies, and may also provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs on treatment.

Significance and Background: Alpelisib plus fulvestrant is approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Identifying patients at risk of developing alpelisib-associated hyperglycemia and proactively tailoring management to the individual will likely result in increased patient compliance and better outcomes of this AE. Innovation: These recommendations for nurses may help optimize hyperglycemia management in patients treated with alpelisib, a relatively new agent.

Current guidance recommends an insulin sensitizer (metformin, thiazolidinedione, DPP-4 inhibitor) at HG onset. Implementation of a HG prevention protocol with ALP in the real-world setting demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated RFs correlated with a higher incidence of G2-4 HG.

Supportive therapy as well as interruption and/or dose reduction were necessary to control treatment-associated side effects. Patient education and a well-trained, interdisciplinary team including diabetologists, from the initiation of alpelisib treatment onwards, are essential to safely treat ABC patients with this new drug and to maintain their quality of life and ensure their survival.

Introduction: Two-thirds of advanced breast cancers are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-). The PFS benefit appears clinically significant over fulvestrant alone, with a 7.9 months, non-significant, improvement in overall survival. Its safety profile requires strict patient selection, mainly based on baseline glycemic status, and close monitoring.

BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative PIK3CA-mutated advanced breast cancer.

P3, Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment for patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation.

PIK3CA-mutated HR+/Her2- mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting.

Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later timepoint. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved PFS at higher alpelisib dose intensities support the need for optimal AE management.

Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup. The study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity.

In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2- mBC that progressed after/on previous AI treatment. Based on the available efficacy and safety data, the "new" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the "old" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2- mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.

PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.

Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA -mutated, HR+, HER2- ABC in the post-CDK4/6i setting.

Background: Somatic genomic alterations that activate the phosphatidylinositol-3-kinase (PI3K) pathway signaling are found in 30-50% of breast cancers, and the p110a-specific inhibitor alpelisib is approved for use in combination with fulvestrant in PIK3CA mutated hormone receptor-positive (HR+) metastatic breast cancer. We report here the feasibility of quantitative and longitudinal detection of activated AKT in EpCAM/Trop2 captured CTCs from metastatic breast cancer with somatic PIK3CA mutations. Future work will prospectively evaluate multiple clinical applications of this assay in patients receiving alpelisib plus endocrine therapy for PIK3CA mutated HR+ metastatic breast cancer, as well as expanding the assay to include the detection of additional phospho-protein readouts of PI3K pathway activity in CTCs. In addition to the potential to complement solid biopsy PIK3CA mutation status as a predictive biomarker of sensitivity to PI3K therapies, this assay has the unique potential to provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs while on treatment, which may serve as an early biomarker of clinical response or resistance.

Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.

The combination of alpelisib with fulvestrant or an aromatase inhibitor such as letrozole is safe and effective with reversible toxicities. Although clinical activity has been observed independently of PIK3CA mutation status, clinical improvement has been mostly seen in a higher proportion of patients with PIK3CA-mutated tumors. In this review I share current data on alpelisib in breast cancer treatment.

Alpelisib in combination with fulvestrant is now available in the clinic for postmenopausal women with advanced or metastatic hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated breast cancer. In addition, promising data has been observed in randomized phase II trials of AKT inhibitors in combination with fulvestrant or paclitaxel in metastatic HR-positive, HER2-negative disease and triple negative breast cancer (TNBC), respectively. The high frequency of genetic alterations in the PI3K pathway has provided the rationale for development of inhibitors targeting PI3K/AKT. Despite initial disappointment with several randomized trials of pan-PI3K inhibitors in HR-positive breast cancer, there has been continued effort to more precisely target PI3K isoforms, which has led to clinical benefit for patients with advanced breast cancer.

Detection of PIK3CA gene mutations in HR+HER2- advanced breast cancer patients allows for the identification of patients who might benefit from more effective personalized treatment with molecularly targeted drugs.

Germline variants were present in a relatively small patient group not routinely tested for inherited alterations. Potentially targetable somatic alterations were identified in the majority of breast cancers. Paired testing is a feasible and efficient approach that delivers valuable information for the care of breast cancer patients and eliminates serial testing.

ctDNA analysis of breast cancer is of clinical utility today in selecting targeted therapy for advanced breast cancer, most notably by assessing PIK3CA mutations in hormone receptor-positive, HER2-negative disease. It will be employed in the near future in a variety of clinical settings including early detection of primary breast cancer, minimal residual disease after initial therapy, and use in advanced breast cancer for prognosis, early identification of non-response, and monitoring genomic markers of resistance.

No abstract available

For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).

Several PI3K inhibitors have been developed and one, alpelisib, was recently approved for use in PIK3CA-mutated, HR+, HER2-negative advanced breast cancer...Additionally, there are several factors to consider for PIK3CA testing in clinical practice, including choice of assay, source of sample, and test timing. In this review, we discuss the use of PIK3CA as a biomarker to guide treatment decisions in patients with HR+, HER2-negative advanced breast cancer, as well as practical considerations and recommendations for testing.

Mutation of TP53 was also associated with incomplete growth suppression in patient subsets treated with either tamoxifen or aromatase inhibitors for EIT (P=0.0005 each)...Funding: The study was supported by a grant from the Deutsche Krebshilfe to SB, MC, and HK (Grant Number 70112954). Clinical trial identification: NCT0177920.