A retrospective analysis of outcomes in metastatic solid tumors harboring alterations in the PI3K pathway as stratified by the presence or absence of diseases of insulin resistance.

e22668 Background: Epidemiologic links are established between diseases of insulin resistance/hyperinsulinemia pre-diabetes mellitus (P-DM) and type 2 diabetes mellitus (T2DM) and increased cancer incidence and worsened oncologic outcomes. The phosphoinositide 3-kinase (PI3K) pathway is central to insulin signaling. Hyperinsulinemia may cooperate with somatic alterations in this pathway to impact clinical outcomes. We hypothesize that patients with either gain of function (GOF) alterations or loss of function (LOF) of major regulators/suppressors (R/S) in the PI3K pathway may have worse clinical outcomes in the setting of P-DM and T2DM. Methods: We performed a retrospective analysis of patients treated at MaineHealth with incurable solid tumors that harbored GOF alterations or LOF of R/S in the PI3K pathway from 1/1/2017-1/1/2024 (sequencing by Tempus (Chicago, IL) and Jackson Laboratory (Bar Harbor, ME)). Patients must have received at least one line of systemic therapy to be included. Overall survival (OS) was measured from the start of systemic therapy to death or last known follow up. Log-rank (Mantel-Cox) test was used for survival analysis. Results: 109 patients were included, 41 with P-DM or T2DM (Insulin Resistant (IR) group) at the time of diagnosis and 68 without (non-IR Group). Median age was 66 years with 59% women in the IR group and 65 years with 68% women in the non-IR group. Mean BMI was 31.0kg/m2 in the IR group and 27.7 kg/m2 in the non-IR group (p=.016). Mean glycosylated hemoglobin (HbA1c) was 7.0% in the IR group and 5.3% in the non-IR group. The most common malignancies in the IR group were NSCLC (27%), colorectal (20%), breast (12%), endometrial (10%), and ovarian (3%) cancer, in contrast to NSCLC (18%), breast (18%), colorectal (12%), endometrial (12%), HNSCC (10%), and ovarian (9%) in the non-IR group. The most common genetic alterations in the IR group were point mutations in PIK3CA (39%), PTEN loss (37%) or PIK3R1 loss (17%), in contrast to PIK3CA (59%), PTEN loss (37%) and PIK3R1 loss (3%) in the non-IR group. For patients with recorded values, ECOG was 0-1 in 76% of the IR group and 88% in the non-IR group. Median survival was 774 days (d) in the IR and 1187d in the non-IR group (Hazards ratio (HR)= 1.65, 95% Confidence interval CI(1.02 to 2.69). In multivariate Cox regression, ECOG was independently associated with survival (ECOG 2–3 vs 0–1: HR 2.50, p=0.003), while female sex was associated with lower hazard (HR 0.52, p=0.016). IR (HR 1.42, p=0.174), age (HR 1.03, p=0.35), and BMI (HR 0.97, p=0.24) were not statistically significant predictors of survival. Conclusions: Patients with metastatic solid tumors harboring GOF or LOF alterations in the PI3K pathway who had P-DM or T2DM showed a trend toward worse OS, although this did not reach statistical significance in multivariate analysis.