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Background:High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women.Methods:This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA).Results:324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia.Conclusions:Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer.Impact:These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Supplementary Table from A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

Background: Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (CGR) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have response enabling interval cytoreductive surgery. Through comprehensive omics analyses, we previously characterized molecular and cellular profiles of highly clinically defined HGSC from patients who had CGR versus those triaged to NACT. However, clinically useful predictive biomarkers for such distinctions are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. Here, we performed extensive molecular characterization of serum-derived EVs and correlated them with therapeutic outcomes in patients with HGSC. Methods: Serum-derived medium/large size EVs from patients with HGSC treated under a systematic surgical algorithm were isolated following standard methods of the International Society for Extracellular Vesicles. Patients had either complete gross resection after primary surgery (R0, n=3); poor response to NACT (NACT-PR, n=4), or excellent response to NACT with carboplatin and paclitaxel (NACT-ER, n=3); tissue and matched germline blood samples have already been comprehensively analyzed (Lee et al, Cell Reports, 2020). The isolated EV-DNA and EV-RNA were subjected to whole-genome sequencing and RNA sequencing, respectively. Results: We identified somatic EV-DNA alterations in cancer hallmark genes, including FAT1 and KMT2D as the most frequent mutated genes. Interestingly, we found alterations in ovarian cancer-related genes, including BRCA2 and RAD51 in R0; BRCA2 in NACT-ER; TP53, CDK13, CDK12, BRAF, AKT2, and ARID1A in NACT-PR patients. We also identified 26,338 genes expressed in the EV-RNA transcriptomic profiles. The analysis of the enrichment of cancer hallmark pathways showed that the R0 group was more enriched in the interferon α/γ, PI3K/AKT/mTOR signaling, and DNA repair pathways. Interestingly, we also identified 6,757 differentially expressed genes (DEGs) in the CGR versus the NACT groups (absolute log2-fold change ≥2 and adjusted p-value Conclusions: Taken together, our preliminary data suggest that molecular characteristics of EVs could provide an accurate prediction of patients with HGSC who can undergo CGR with surgery and respond to chemotherapy. Citation Format: Li Zhao, Shaolin Ma, Nicole D. Fleming, Joseph Celestino, Mark S. Kim, Richard A. Hajek, Nicholas B. Jennings, Erika J. Thompson, Hongli Tang, Shannon N. Westin, Amir A. Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K. Sood, Sanghoon Lee. Distinct molecular profiles of serum-derived extracellular vesicles in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5106.

Background: High-grade serous ovarian cancer (HGSC) is the most aggressive epithelial ovarian cancer, exhibiting tumor heterogeneity, molecular abnormality, and variable clinical outcomes. The heterogeneity and apparent adaptability of the HGSC genome under selective pressure by chemotherapy likely explain the high rates of drug resistance in HGSC. However, the underlying mechanisms of drug resistance are not well understood. Following our previous findings of significant distinct molecular and cellular characteristics in pre-treatment tumor samples from highly clinically annotated HGSC patients who received neoadjuvant chemotherapy (NACT), we examined post-treatment transcriptomic changes associated with excellent or poor responders to NACT in HGSC patients. Methods: Thirty tumor tissues (pre- and post-treatment) after 3 to 4 cycles of NACT were collected from HGSC patients at interval cytoreductive debulking surgery from the following groups: excellent response to NACT with carboplatin/paclitaxel (post-ER, n=8); poor response to NACT (post-PR, n=8). Primary or metastatic sites for each patient were obtained (n=13, post-ER; n=17, post-PR) and subjected to RNA sequencing. The downstream bioinformatics analysis was then performed and compared with the data from the matched pre-NACT samples from the same patients (Lee et al., Cell Reports, 2020). Results: We identified a total of 9,764 upregulated and 2,762 downregulated differentially expressed genes (DEGs, absolute log2FC >=2, adj-p Conclusions: Our transcriptomic analysis revealed distinct transcripts changes in post-NACT vs pre-NACT tumor tissues from HGSC patients with excellent or poor response to the NACT. These findings could enhance treatment decision-making and rationale for developing alternative therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Yan Liu, Shannon N. Westin, Amir A. Jazaeri, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5738.

Background: Despite high rates of remission after frontline management, most patients with advanced stage ovarian cancer recur. Second look laparoscopy (SLL) can provide more sensitive detection of minimal residual disease (MRD) allowing for more individualized prognostication and possible therapeutic intervention. It may also assess tumor biology and microenvironment associated with undetectable chemoresistant MRD phase of ovarian cancer. The objective of this study was to determine SLL feasibility, and clinicopathologic and molecular characteristics of MRD after frontline therapy in ovarian cancer. Methods: SLL was offered to patients with stage III-IV high grade epithelial ovarian cancer who achieved complete response after frontline surgery and 6 cycles of carboplatin and paclitaxel chemotherapy. Patients were offered standard of care or investigational management options based on homologous recombination deficiency (HRD) and MRD status at SLL. Preliminary translational studies included RNAseq for comparison of serial, matched tumor from primary or interval TRS and SLL derived MRD+ biopsies at the time of SLL. In addition, Nanostring analyses of SLL surgical biopsies both with and without residual tumor were performed. Molecular profiling employed hierarchical clustering, principle component analysis, non-parametric testing, and pathway analyses. Results: Between 4/2017- 7/2021, 39 patients underwent SLL. The majority had stage III disease (74%), high grade serous histology (90%) and underwent neoadjuvant chemotherapy with interval tumor reductive surgery (TRS; 54%). MRD was present in 49% (n=19) of patients and was more frequent among neoadjuvant chemotherapy recipients (73% vs 26%, P=0.015) and patients with homologous recombination proficient tumors (81% vs 25%, P=0.01). Most patients without MRD were dispositioned to observation; 4 patients with HRD received a PARP inhibitor per standard of care. All other patients with MRD received bevacizumab as part of a clinical trial, except for one patient who received a PARP inhibitor. Median follow-up was 6.74 months (range 0.66 - 28.62). Presence of MRD was associated with worse PFS (HR 3.7, 95% CI 1.3- 10.9; 5.5 vs 24.6 months; P= 0.02). Based on transcriptional signature, MRD are immunologically distinct from untreated tumors or those collected at interval TRS (after 3 cycles of chemo) but also displayed heterogeneity with two distinct subclusters. Conclusions: SLL to assess for MRD has potential to further individualize post-frontline therapy, and identify patients at high risk for progression for early intervention clinical trials. Transcriptional profiling suggests that MRD phase of ovarian cancer is characterized by a distinct, heterogeneous, and evolving tumor and immune microenvironment. Citation Format: Roni Nitecki, Minghao Dang, Sanghoon Lee, Bryan Fellman, J Alejandro Rauh-hain, Jolyn Taylor, Lois Ramondetta, Michaela Grinsfelder, Lauren Cobb, David M. Boruta, Pamela T. Soliman, Aaron Shafer, Nicole D. Fleming, Shannon N. Westin, Anil K. Sood, Chris Tanguma, Pedro T. Ramrez, Karen H. Lu, Linghua Wang, Amir A. Jazaeri. Initial clinicopathologic and molecular characterization of minimal residual disease detected by second look laparoscopy after completion of frontline surgery and chemotherapy in patients with advanced stage ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4135.

Background: While high-grade serous ovarian cancers (HGSC) look alike at a histological level, there is marked variation in clinical outcomes; however, the underlying mechanisms are not well understood. We previously highlighted significant distinct molecular and cellular characteristics in highly clinically annotated HGSC tumor samples from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT). Neurofibromatosis type 1 (NF1) is known to negatively regulate the Ras/MAPK signaling pathways and tumorigenesis. Here, we specifically validate the higher loss of NF1 copy number exhibited in the R0 compared to the NACT groups in patients with HGSC. Methods: Fresh-frozen tumor biopsies were collected from patients with HGSC treated under a systematic surgical algorithm: complete gross resection after primary surgery (R0, n=40); poor tumor response to NACT (NACT-PR, n=26); excellent tumor response to NACT with carboplatin and paclitaxel (NACT-ER, n=14). Primary or metastatic tumor sites for each patient were obtained pre-treatment and subjected to high-depth targeted DNA sequencing. Results: The average coverage of 568X for tumors and 291X for germline controls (matched blood samples) was obtained by targeted sequencing for each sample from the entire cohort. The median numbers of non-synonymous somatic mutations identified in the panel sequencing were 5 in R0, 3 in NACT-ER, and 5 in NACT-PR. Sixty-nine of the 80 samples (86.25%) had alterations in at least one of the ovarian cancer-related genes. The most frequently altered genes including somatic mutations and copy number variations were TP53 (68%), NF1 (65%) and ERBB2 (62%) in the R0 group whereas TP53 (50%), AKT1 (48%) and TERT (42%) in the NACT group. Gene alteration enrichment was evaluated by comparing between two groups. 17 genes were found to be enriched for alterations in the R0 group comparing to the NACT group; MLH3 (OR= 15.03, p Conclusions: Our findings, using an independent validation cohort of patients, verified the higher loss of NF1 copy number in the R0 versus the NACT group. These findings could have major implications for clinical decision making and developing novel therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Mark S. Kim, Shannon N. Westin, Amir A. Jazaeri, Nicole D. Fleming, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. NF1 copy number alterations in clinically-defined subsets of high-grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2200.

Objectives: To evaluate safety and efficacy of durvalumab (D) in combination with paclitaxel (P) and carboplatin (C) in newly diagnosed, advanced-stage, high grade, non-mucinous ovarian cancer (OC). To investigate informative pharmacodynamic changes including proteome changes and immune-related pathways by treatment with immuno-oncology therapy in combination with chemotherapy. Methods: In this single arm phase II study, patients (pts) with untreated, advanced stage (III/IV) OC dispositioned to neoadjuvant chemotherapy (NACT) received D (750mg) with weekly P (80mg/m2) and C (AUC6) after baseline tissue biopsy. Matched biopsies were obtained at tumor reductive surgery (TRS) after 3 cycles. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Reverse-phase protein arrays (RPPA) were performed on pre- and post-treatment tissues. Protein expression alteration and an enriched Reactome pathway analysis using differentially expressed proteins between pre- and post-treatments were assessed. Results: 19 pts were enrolled and 18 treated. Median age was 63 and 50% had stage III disease. No dose-limiting toxicities were observed. 94% of pts had an adverse event (AE). Most common AEs were anemia (94%), neutropenia (83%), fatigue (72%), hyperglycemia (73%), and thrombocytopenia (66%). Immune-related AEs observed included hyperthyroidism (22%), hypothyroidism (22%), diarrhea (6%), hypophysitis (6%). Eighty-three percent had optimal interval TRS, 70% had a pre-operative response by RECIST (PR=11, CR=1). At 13 months (mo) median follow up, 9 pts (50%) had disease progression and median PFS was 14.5 mo (95% CI: 9.2 - NA). Median OS was not reached; OS rate at 18 mo was 69% (95% CI 0.21 - 0.91). Fifty-five tumor specimens were available from 9 pts (31 pre- and 24 post-treatment). Thirteen significantly differentially expressed proteins among 211 proteins (adj. p Citation Format: Shannon N. Westin, Sanghoon Lee, Li Zhao, Ying Yuan, Jimin Wu, Richard Hajek, Sara Sharafi, Larissa A. Meyer, Nicole D. Fleming, Amir Jazaeri, Robert L. Coleman, Karen H. Lu, Gordon B. Mills, Jianhua Zhang, Andrew Futreal, Anil K. Sood. Pharmacodynamic changes by durvalumab in combination with chemotherapy in women with untreated, advanced stage ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT188.

Background: Prior molecular characterization efforts for high-grade serous ovarian cancer (HGSOC) were restricted to those who had upfront surgical debulking with variable treatment paradigms. Thus, we sought to examine molecular and cellular differences between clinically defined groups (tumor tissues from patients who had complete gross resection (CGR) versus those who were triaged to neoadjuvant chemotherapy (NACT) and experienced either excellent or poor response. Methods: Tumor biopsies were collected from three patient groups managed under a systematic surgical algorithm: CGR after primary surgery (R0, n=10); poor tumor response to NACT (NACT-PR, n=10); excellent tumor response to NACT (NACT-ER, n=10). Primary and multiple metastatic tumor sites per each patient were obtained pre-treatment and subjected to comprehensive omics analyses including high-pass whole-genome (WGS) and targeted deep DNA sequencing. Results: An average of 71 nonsynonymous somatic mutations from each sample for 75 samples with high-purity tumors (≥75%) by WGS were identified from each sample for the entire cohort. Fourteen ovarian-cancer-associated genes were found mutated in our patient cohort and, as expected, the most frequently mutated gene was TP53 in both primary and metastatic sites in all three groups. TP53 nonsense mutations were exclusively identified in the NACT-ER (36.0%) and NACT-PR groups (15.4%), while in the R0 group most TP53 mutations were missense mutations (62.5%). Nonsense mutations in CSMD3 and PIK3CA were exclusively identified in both primary and metastatic sites in the NACT-PR group. The most frequent copy number variations (CNVs) in the R0 were copy number gain/loss of CSMD3 (67%) and copy number loss of NF1 (54%) and CDK12 (50%) in both primary and metastatic sites. Interestingly, copy number losses of NF1 were significantly lower in the NACT groups (18%, p=0.002), especially in the NACT-PR (8%, p=0.0004), when compared to the R0 group (54%). We also identified significant less observation of chromothripsis-like patterns, and a significantly higher level of strong-binding neoantigens in the R0 than in the NACT groups. Conclusions: Our findings using HGSOC samples obtained from patients treated on a prospective algorithm identified distinct molecular abnormalities, and could have prognostic and therapeutic implications for patients with HGSOC. Citation Format: Sanghoon Lee, Li Zhao, Shannon N. Westin, Nicholas W. Bateman, Amir A. Jazaeri, Nicole D. Fleming, Karen H. Lu, Robert L. Coleman, Gordon B. Mills, Jianhua Zhang, Thomas P. Conrads, George L. Maxwell, P. Andrew Futreal, Anil K. Sood. High-depth whole genome sequencing of clinically-annotated high-grade serous ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2510.

Background: High-grade serous ovarian cancer (HGSOC) remains the leading cause of death from gynecologic malignancies. Here, we examined tumoral proteome changes following neoadjuvant chemotherapy (NACT) to identify potential predictive and prognostic biomarkers of response to primary chemotherapy. Methods: A total of 65 tissue specimens from 10 patients with advanced-stage HGSOC were collected from matched pre- and post-NACT (3 cycles of dose-dense paclitaxel and carboplatin). Protein expression was assessed using reverse-phase protein arrays (RPPA). All relative protein levels using 297 antibodies were normalized by the expression level of pre-treatment samples, and then protein expression alterations and functional analyses were performed by Reactome pathway analysis followed by statistical analysis. Results: The protein expression patterns of samples tended to cluster according to the time point (pre- and post-treatment) by a non-supervised clustering analysis using all the proteins assessed in the RPPA panel. Five differentially expressed proteins among 239 proteins (adj. p Conclusion: Our findings identified significant proteomic alterations following NACT, and could provide insights into interval proteomic alterations following induction chemotherapy in advanced-stage ovarian cancer patients. These data present information to optimize future clinical trial designs for patients with ovarian cancer. Citation Format: Sanghoon Lee, Li Zhao, Joseph Celestino, Kelly M. Rangel, Richard A. Hajek, Mark S. Kim, Sara E. Sharafi, Jinsong Liu, Nicole D. Fleming, Karen H. Lu, Jianhua Zhang, P. Andrew Futreal, Gordon B. Mills, Shannon N. Westin, Anil K. Sood, Amir A. Jazaeri, Robert L. Coleman. Functional proteomic aberrations post-chemotherapy with paclitaxel and carboplatin in patients with advanced ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2941.