Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer

Abstract

Background Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment. Methods We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan–Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ2 test and Kruskal–Wallis rank sum test. Cox regression was used for univariate and multivariable analyses. Results We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3–26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8–10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8–13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1–not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7–12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8–24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42–3.96; P < 0.001). Conclusions The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.

Cell senescence-associated genes predict the malignant characteristics of glioblastoma

“…But interestingly, TP3, the somatic mutation rate was as high as 63% in the low-risk group, which is a tumor suppressor gene with the function of regulating cell division and proliferation. The association of TP53 mutations with the development of a variety of tumors has been well documented [ 34 , 35 ]. Therefore, further research is needed.…”

Advancements in the treatment of metastatic hormone-sensitive prostate cancer

“…Velez et al found that the median PFS was 13.1 months in the TSG-normal group vs 7.8 months in the TSGaltered group (p = 0.005); subgroup analysis showed that the median PFS was lower in TSG-altered patients compared to TSG-normal patients in the abiraterone+ADT group (8.0 months, 95% CI 5.8-13.8; 23.2 months, 95% CI 13.1-NA), but no difference was observed between the docetaxel+ADT subgroups. Using multivariable analysis, Velez et al reported that altered TSG predicted the prognosis of mHSPC in early first-line treatment (HR: 2.37, 95% CI 1.42-3.96; p < 0.001) and that detection of the TSG mutation was superior to the clinical criteria (61). However, several gene mutations benefit from hormonal therapy.…”

“…As gene mutations are significantly associated with the prognosis of metastatic castration-resistant prostate cancer (mCRPC) ( 58 – 60 ), previous studies have also reported the relationship between gene mutation and mHSPC ( 61 – 63 ). Velez et al.…”

“…Using multivariable analysis, Velez et al. reported that altered TSG predicted the prognosis of mHSPC in early first-line treatment (HR: 2.37, 95% CI 1.42–3.96; p < 0.001) and that detection of the TSG mutation was superior to the clinical criteria ( 61 ). However, several gene mutations benefit from hormonal therapy.…”

The impact of genetic aberrations on response to radium‐223 treatment for castration‐resistant prostate cancer with bone metastases

“…Tumor genomics play an increasingly important role in determining standard of care in prostate cancer. Many recurrent gene alterations have been shown to have prognostic significance (e.g., TP53, RB, PTEN, and TMPRSS2-ERG), [1][2][3][4][5] and treatments such as poly ADPribose polymerase inhibitors and platinum based therapies are now approved for the treatment of cancers with specific DNA damage response (DDR) mutations. 6,7 Mutations of genes that govern DDR in prostate cancer have been associated with aggressive behavior and poor prognosis.…”