Clinical and genomic features of SPOP-mutant prostate cancer.

BACKGROUND: Inactivating missense mutations in the SPOP gene, encoding speckle-type poxvirus and zinc-finger protein, are one of the most common genetic alterations in prostate cancer. METHODS: We retrospectively identified 72 consecutive prostate cancer patients with somatic SPOP mutations, through next-generation sequencing analysis, who were treated at the Johns Hopkins Hospital. We evaluated clinical and genomic characteristics of this SPOP-mutant subset. RESULTS: SPOP alterations were clustered in the MATH domain, with hotspot mutations involving the F133 and F102 residues. The most frequent concurrent genetic alterations were in APC (16/72 [22%]), PTEN (13/72 [18%]), and TP53 (11/72 [15%]). SPOP-mutant cancers appeared to be mutually exclusive with tumors harboring the TMPRSS2-ERG fusion, and were significantly enriched for Wnt pathway (APC, CTNNB1) mutations and de-enriched for TP53/PTEN/RB1 alterations. Patients with mtSPOP had durable responses to androgen deprivation therapy (ADT) with a median time-to-castration-resistance of 42.0 (95% confidence interval [CI], 25.7-60.8) months. However, time-to-castration-resistance was significantly shorter in SPOP-mutant patients with concurrent TP53 mutations (hazard ratio [HR] 4.53; p = 0.002), HRD pathway (ATM, BRCA1/2, and CHEK2) mutations (HR 3.19; p = 0.003), and PI3K pathway (PTEN, PIK3CA, and AKT1) alterations (HR 2.69; p = 0.004). In the castration-resistant prostate cancer setting, median progression-free survival was 8.9 (95% CI, 6.7-NR) months on abiraterone and 7.3 (95% CI, 3.2-NR) months on enzalutamide. There were no responses to PARP inhibitor treatment. CONCLUSIONS: SPOP-mutant prostate cancers represent a unique subset with absent ERG fusions and frequent Wnt pathway alterations, with potentially greater dependency on androgen signaling and enhanced responsiveness to ADT. Outcomes are best for SPOP-altered patients without other concurrent mutations.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

Case Series of Men with the Germline APC I1307K variant and Treatment-Emergent Neuroendocrine Prostate Cancer.

INTRODUCTION: Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. MATERIALS AND METHODS: We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. RESULTS: From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). CONCLUSION: PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.

Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC.

Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection. SIGNIFICANCE: Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures.

BACKGROUNDImmune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.METHODSIn an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs.RESULTSWe enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade ≥ 2). Development of a grade ≥ 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-α) cytokine signatures and congruent on-treatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade ≥2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival.CONCLUSIONSIn a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions.FUNDINGJohns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY).

Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Delta Variant Shedding in a Patient With AIDS: Case Report and Review of the Literature.

We describe the case of a patient with AIDS who had persistent infection with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant for >80 days. The variant contained mutations that were not present in other Delta viruses in our hospital. Prolonged infection in immunosuppressed individuals may lead to evolution of SARS-CoV-2 lineages.