Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). METHODS: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. RESULTS: 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. CONCLUSION: Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.

Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor-Positive Breast Cancer.

PURPOSE: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. RESULTS: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. CONCLUSIONS: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer.

OBJECTIVES: Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. METHODS: Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. RESULTS: Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. CONCLUSION: UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen.

PD-L1 Expressing Recurrent Clear Cell Carcinoma of the Vulva with Durable Partial Response to Pembrolizumab: A Case Report.

BACKGROUND: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. CASE PRESENTATION: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. CONCLUSION: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer.

OBJECTIVE: Tumor gene expression signatures have been used to classify, prognosticate, and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short-term and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures. METHODS: Using a set of 47 breast cancer patients, we obtained paired prechemotherapy and postchemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), postchemotherapy tumor (T2), and chemotherapy-induced relative change signatures (TDelta) to predict pathological response and progression-free survival (PFS). The signatures were validated in two independent test sets with paired prechemotherapy and postchemotherapy tumor samples, comprising of 18-20 patients each. RESULTS: T2 and TDelta were superior to T1 signatures in predicting for PFS (area under the curve of receiver operating characteristic 0.770 and 0.660 vs. 0.530) and pathological response (area under the curve of receiver operating characteristic 0.631 and 0.462 vs. 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2, but not T1, signatures remained as significant independent predictors. CONCLUSION: Postchemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.

Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.

BACKGROUND: Developing multiple cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the clinical genetic testing outcomes of these patients. METHODS: We compared cancer index patients with ≥2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multi-gene panels comprising up to 49 genes from 1998-2016. RESULTS: Among 1191 cancer index patients, 80.6%, 17.2%, and 2.2% respectively had 1, 2, and ≥3 primary malignancies. For patients with 2 primary cancers (n=205), the most common cancer pairs were bilateral breast (37.5%), breast-ovary (11.7%), endometrium-ovary (9.2%), colon-endometrium (3.9%) and colon-colon (3.4%). 42.3% patients underwent gene testing including 110/231 (47.6%) with multiple malignancies. Pathogenic variants were found more frequently in younger patients, in those with a family history of cancer related to the suspected syndrome, and a trend towards significance in those with multiple primary cancers (35.5% vs. 25.6%, p = 0.09). In patients with multiple cancers, pathogenic variants were most commonly identified in BRCA1 (38.5%), BRCA2 (17.9%), and the mismatch repair genes (20.5%), while 23.1% of pathogenic mutations were in other moderate- to high-penetrance cancer predisposition genes including APC, ATM, MUTYH, PALB2, RAD50 and TP53. CONCLUSION: Patients with multiple cancers were more likely to carry pathogenic mutations than those with single cancer. About three-quarters of deleterious mutations in patients with multiple primary cancers were in BRCA1/2 and the mismatch repair genes, but multi-gene panel testing facilitated the detection of mutations in another 6 genes and is warranted in this high-risk population.

Chemotherapy-induced tumor gene expression changes in human breast cancers.

OBJECTIVE: Studying chemotherapy-induced gene expression changes in vivo, which could provide insights into mechanisms of chemotherapy resistance. METHODS: We analyzed and compared tumor gene expression changes of about 38 500 genes before and 3 weeks after doxorubicin or docetaxel treatment in 47 breast cancer patients. RESULTS: By using the median expression level of each probe set as the parameter, less than 5% of genes were upregulated or downregulated by more than 50% after treatment with either drug. Doxorubicin and docetaxel concordantly induced 251 genes predominantly involved in protein and macromolecule metabolism (upregulated), and cell cycle and DNA/RNA metabolism (downregulated). Doxorubicin treatment resulted in coregulation of a cluster of 345 probe sets involved in focal adhesion, Jak-Stat signaling pathway, cell adhesion molecules, and natural killer cell mediated cytotoxicity, whereas docetaxel treatment resulted in coregulation of a cluster of 448 probe sets involved in focal adhesion, neurodegenerative disorders, sphingolipid metabolism, and cell cycle. Tumors that were intrinsically sensitive or resistant to doxorubicin or docetaxel evoked distinct gene expression changes in response to the drug; doxorubicin-resistant tumors upregulated genes that were enriched for ErbB signaling, ubiquitin-mediated proteolysis, TGF-beta signaling, and MAP-kinase signaling pathways, whereas docetaxel-resistant tumors upregulated genes that were enriched for focal adhesion and regulation of actin cytoskeleton. The drug-specific tumor gene expression changes were validated in independent in-vitro and in-vivo datasets. CONCLUSION: Gene expression alterations of breast cancer were specific to doxorubicin and docetaxel treatment, and yielded mechanistic insights into resistance to either drug. Gene expression analysis provides more global perspectives on resistance pathways that could be exploited for therapeutic selection.