PTEN Alterations Research Articles

Abstract OT2-08-02: Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290)

Abstract Background: Triple-negative breast cancer (TNBC) generally has an aggressive clinical course, including distant metastases and increased likelihood of death within 5 years of diagnosis compared with non-TNBCs. Therapeutic options for metastatic TNBC patients are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in germline BRCA-mutant patients). However, improvements in progression-free survival (PFS) derived from immune-oncology and PARP inhibitors are still insufficient in terms of informing patient selection and overall magnitude of benefit. Developing novel treatments in both early and advanced TNBC settings remains a significant unmet need in the management of advanced breast cancer. The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The Phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer PFS and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid, 2018). The Phase III trial we report (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2-5, 9-12, 16-19) every 28 days until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity, or death. Stratification factors will be prior adjuvant chemotherapy, visceral vs non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study opened in May 2019. Citation Format: Peter Schmid, Javier Cortes, Mark Robson, Hiroji Iwata, Roberto Hegg, Sunil Verma, Marina Nechaeva, Binghe Xu, Vincent Haddad, Esteban Rodrigo Imedio, Gaia Schiavon, Andrew Foxley, Yeon Hee Park. Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-08-02.

Abstract P4-09-04: Prevalence of phosphatidylinositol-3-kinase (PI3K) pathway alterations and co-alteration of other markers in breast cancer

Abstract Background: PI3K/AKT signaling pathway is often activated in breast cancer (BC), through mutations in PIK3CA or AKT1, and alterations in PTEN, thus promoting cell survival. PI3K and AKT inhibitors have been shown to have significant activity against tumor progression and to overcome resistance in BC. We aim to explore the prevalence of PI3K pathway alterations and co-expression with other markers in different BC subtypes. This approach could allow identification of novel drug combinations that have the potential to elicit synergistic growth inhibition and be further explored in the clinical trial setting. Methods: Molecular profiles of 4895 female and male BC cases submitted to Caris Life Sciences were reviewed to identify pathogenic or presumed pathogenic mutations in PIK3CA, AKT1, PTEN, PIK3R1 and PIK3R2 using 592-gene next generation sequencing (NGS; average read depth 500 ×). Cases with loss of PTEN by IHC were also included. Co-mutation frequency with PIK3CA-AKT1-PTEN alterations were examined, including homologous recombination deficiency (HRD) genes and DNA damage response (DDR) pathways, markers of response to immune-oncology (IO) agents and RAS signaling pathway. Cases were classified in BC subtypes according to the ASCO-CAP guidelines. Results: The median age was 58 (range: 17-90). Gender frequency and primary/ metastatic site frequency were similar across BC subtypes. 3558 (72.7%) cases had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1472 (30.1%) cases harbored a PIK3CA mutation, 174 (3.6%) harbored an AKT1 mutation, and 2682 (54.8%) had PTEN alterations (PTEN mutation in 344, 7.0% and/or PTEN loss by IHC in 2516, 51.4% of cases). The most common hotspot mutations in PIK3CA were in the kinase domain (H1047R in 567 cases, 38.5% of all PIK3CA alterations) and in the helical domain (E545K in 304 cases, 20.7% of all PIK3CA alterations). Uncommon activating PIK3CA mutations were seen in 8.4% of breast tumors. The single hotspot mutation, E17K, was the most common AKT1 mutation (n=164, 94.3% of all AKT1 mutations). 81 (1.7%) tumors harbored a PIK3R1 mutation, with 66 unique alterations identified (4 pathogenic, 55 presumed pathogenic), and 4 (0.08%) cases harbored a PIK3R2 mutation (G373R mutation). With respect to the different BC subtypes, PIK3CA was the most frequent alteration in HER2 positive BC (present in 96.2% of mutated cases). Within HER2 negative subtypes, PTEN was most frequently altered and PTEN mutation or PTEN loss by IHC was present in 79.3% of mutated cases. Triple negative breast cancer (TNBC) was the subtype with the lowest frequency of PIK3CA mutations (18.0% in TNBC vs. 37% in other subtypes). The frequency of selected co-mutations with PIK3CA-AKT1-PTEN alterations is illustrated in table 1. Notable co-alterations in this cohort include increased PD-L1 expression and high tumor mutational burden (TMB). There were no significant increases in the frequency of mutations in DDR pathway mutations (not shown) in the PIK3CA-AKT1-PTEN altered cohort. Conclusions: We observed a high prevalence of expected hotspot mutations in PIK3CA and AKT1 across BC subtypes. There was a significant increase in PD-L1 expression in tumor cells, and high TMB in PIK3CA-AKT1-PTEN mutated cohorts. A similar association was seen with RAS signaling pathways. Further development of drugs that affect the PIK3CA-AKT1-PTEN pathway in all BC subtypes and combination with drugs that target the immune system may be of interest. Table 1. Selected co-alterations based on statistical significancePathwayGene/ ProteinAll subtypes (%)HR+ HER2+ (%)HR- HER2+ (%)HR+HER2- (%)TNBC (%)MTWTMTWTMTWTMTWTMTWTHomologous recombinationBRCA13.02.71.00.60.00.80.8*1.8*6.16.0BRCA24.15.41.02.53.62.34.1*7.9*4.43.0PALB20.7*1.3*0.00.00.00.00.5*2.5*0.90.3Possible predictors of IO benefitPD-149.850.038.552.266.766.737.541.766.058.1PD-L1 (SP142)6.9*4.2*3.30.78.14.93.33.011.68.1(Tumor Cells)PD-L1 (SP142)29.226.650.018.825.027.312.916.742.140.4(Immune Cells)MSI0.70.60.00.01.20.80.80.40.71.2TMB-High (≥ 10 mut/Mb)22.9*18.8*36.0*17.2*29.825.921.2*16.6*23.621.3Chromatin remodelingARID1A12.4*18.6*19.423.87.118.917.121.55.89.6ARID20.70.80.01.90.00.70.80.60.60.9RAS-RAF-MEK-ERK HRAS0.7*0.1*0.00.00.00.00.20.11.40.3KRAS2.0*1.1*1.00.00.00.01.91.22.22.0NRAS0.20.00.00.00.00.00.20.00.30.0BRAF0.50.11.00.01.20.00.60.30.40.0OthersTP5360.9*53.1*66.360.885.586.738.4*25.6*84.786.4CDH110.3*6.1*9.1*2.5*4.82.215.1*9.6*4.9*2.3*NF16.2*2.1*9.5*0.8*2.73.65.8*1.8*6.7*2.8*RB15.5*2.6*2.21.33.63.03.9*1.7*7.85.0ERBB22.3*3.4*3.03.13.56.73.23.51.0*2.3*Notes: MT = at least 1 pathogenic mutation in PIK3CA, AKT1, or PTEN or PTEN loss by IHC. WT = no pathogenic mutations in PIK3CA, AKT1, and PTEN.*statistically significant difference between MT and WT Citation Format: Katia Khoury, Antoinette Tan, Andrew Elliott, Joanne Xiu, Zoran Gatalica, Arielle L Heeke, Claudine Isaacs, Paula R Pohlmann, Lee S Schwartzberg, Michael Simon, Michael W Korn, Sandra M Swain, Filipa Lynce. Prevalence of phosphatidylinositol-3-kinase (PI3K) pathway alterations and co-alteration of other markers in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-04.

Abstract P6-08-03: Germline mutational landscape in 5422 individuals at risk for hereditary breast and ovarian cancer who underwent multi-gene panel testing

Abstract Background: The introduction of multi-gene panel testing and improved awareness under patients and physicians has led to an increase of individuals with known germline pathogenic variants in hereditary breast and ovarian cancer (HBOC) genes. Significant regional differences exist in germline mutational landscape. We aimed to report the findings from multi-gene panel testing in a large Belgian cohort of individuals at risk for HBOC. Methods: All individuals who underwent multi-gene panel testing for HBOC at the Center for Human Genetics of the University Hospitals Leuven since the introduction of the panel were included (March 2016-April 2019). All included individuals were considered candidates for HBOC-panel testing by the requesting physician based on a personal or familial history of breast and/or ovarian cancer. Testing criteria from the Belgian Society of Human Genetics (www.beshg.be/download/guidelines/Guidelines_HBOC_2018.pdf) were met in the vast majority. The panel used was the BRCA Hereditary Cancer MASTR Plus® (Agilent, Belgium), with sequencing of BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2 and MSH2. Sequencing was performed by NGS on a Miseq platform (Illumina). Genomic deletions and duplications in BRCA1 and BRCA2 were investigated with multiplex ligation-dependent probe amplification. We hereby report on the frequency of pathogenic and likely pathogenic germline variants in this population. Results: In 5422 individuals who underwent multi-gene panel testing, we detected 665 pathogenic or likely pathogenic variants in 639 patients (11,7%). In 25 patients (0.46%), more than one relevant alteration was detected with double heterozygosity in 24 individuals and triple heterozygosity in one. Germline variants in BRCA1 and BRCA2 were detected in 178 (3.3%) and 144 (2.7%) patients, resulting in a fraction of 26,4% and 21,4% of detected variants respectively. Relevant alterations in CHEK2, ATM, PALB2 and TP53 were observed in 135 (2.5%), 93 (1.7%), 26 (0.5%) and 11 (0.2%) patients respectively, accounting together for 39.3% of detected variants. Alterations in BRIP1/RAD51C/RAD51D were retrieved in 64 patients (1.2%) and alterations in mismatch-repair genes MSH6/MLH1/PMS2/MSH2 were detected in 0.3% of patients. These patients where dominantly referred for familial history of ovarian cancer. Furthermore, germline alterations in PTEN, CDH1 and BLM were observed in 3, 2 and 1 cases respectively. Double heterozygosity for ATM+CHEK2 and for ATM+BRCA2 were both observed in 3 cases. In the patient with triple heterozygosity, co-occurrence of pathogenic variants in BRCA2, ATM and CHEK2 was detected. Conclusions: In a large Belgian cohort of 5422 individuals at risk for HBOC who underwent multi-gene panel testing, a pathogenic or likely pathogenic germline variant was detected in 11,7% of patients, and in 0,46% of patients double or triple heterozygosity for HBOC-variants was observed. Almost 40% of detected variants were alterations beyond BRCA correlated with hereditary breast cancer (CHEK2, ATM, PALB2 and TP53). Given the time-lag to predictive testing in families, a significant rise in healthy carriers with these non-BRCA alterations is expected in the upcoming years. Citation Format: Kevin Punie, Griet Hoste, Griet Van Buggenhout, Ellen Denayer, Hilde Brems, Hilde Peeters, Ann Smeets, Ines Nevelsteen, Patrick Neven, Jan Ardui, Renate Prevos, Machteld Keupers, Chantal Van Ongeval, Giuseppe Floris, Christine Desmedt, Hans Wildiers, Geneviève Michils, Hilde Van Esch, Eric Legius. Germline mutational landscape in 5422 individuals at risk for hereditary breast and ovarian cancer who underwent multi-gene panel testing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-03.

Abstract P4-10-20: Protein quantitation assays for AKT and PTEN to better understand sensitivity and resistance of breast cancer patients to treatment with AKT inhibitor capivasertib

Abstract Context: The PI3K/AKT/PTEN pathway is frequently aberrantly activated in breast cancer (BC) and involved in resistance to hormonal therapy. Multiple drugs targeting this pathway are approved or in development, including the pan-AKT inhibitor capivasertib (AZD5363). Early phase studies of capivasertib as monotherapy for solid cancers (e.g. NCT01226316, NCT01625286) have used genetic testing to select patients considered most likely to respond based on AKT1, PIK3CA or PTEN mutations. However, not all selected patients responded. Randomised phase 2 studies on Capivasertib as combination treatment showed the importance of context; a more pronounced response in combination with paclitaxel was seen in TNBC patients whose tumors harboured an alteration on AKT1, PIK3CA or PTEN (Schmid et al. ASCO 2018), whereas the same combination in ER+ HER2- advanced/metastatic BC patients did not show a clinical benefit in the overall population nor in the PIK3CA-mutation subgroup (Turner et al. Ann Oncol 2019). The combination with fulvestrant demonstrated an effect in unselected ER+ HER2- advanced BC patients resistant to aromatase inhibitors irrespective of PIK3CA mutations or PTEN IHC status (Jones et al. ASCO 2019). DNA-based assays also have the limitation that potential responders may be missed, e.g., tumors with epigenetic pathway activation but no detectable mutations. Techniques such as IHC and Western Blot (WB) lack the sensitivity, reproducibility and standardization required to precisely quantify these proteins. We hypothesize that precise mass spectrometry (MS)-based methods may facilitate a better understanding of sensitivity and resistance to inhibitors of the PI3K/AKT pathway in future studies. Methods: Protein extracted from tumor tissue lysate is subjected to proteolytic digestion to generate proteotypic peptides used for protein quantitation. Synthetic stable isotope-labeled peptides are added to the digest as an internal standard, after which the target peptides are immuno-enriched with antibodies coupled to magnetic beads. MS analysis is performed by either eluting peptides for measurement with liquid chromatography multiple reaction monitoring tandem MS (LC-MRM-MS/MS) or by spotting beads onto a plate for matrix-assisted laser desorption/ionization MS (MALDI-MS). Calibration curves enable accurate quantitation. A new method for PTEN was applied to 13 breast cancer PDXs. Results were compared to IHC and WB. In a retrospective study, we are applying these methods to test samples from HR+ metastatic breast or gynecological cancer patients (n=25 with PIK3CA-mutations, capivasertib monotherapy; n=26 with PTEN alterations, capivasertib + fulvestrant; n=9 with no PIK3CA, AKT1 or PTEN mutations, not receiving capivasertib). AKT and PTEN quantitation data will be analyzed for a relationship to treatment response as determined by RECIST guidelines (NCT01226316). Results: We validated MS methods to precisely and reproducibly determine AKT and PTEN concentrations in tumor samples. AKT concentrations varied significantly between mutation-positive tumor samples (AKT1: 0.06-0.45, AKT2: 0.05-0.20 fmol/µg total protein). Significant phosphorylation of AKT1-Ser473 or AKT2-Ser474 was observed in 2 out of 17 tested samples. At least 1 mutation-negative sample had a high AKT1 concentration of 0.42 fmol/ug total protein. PTEN concentrations from PDXs were consistent across biological replicates and agreed with IHC and WB. Furthermore, we were able to detect and quantify PTEN from 3 samples that were negative by IHC and/or WB. Conclusion: AKT and PTEN quantitative proteomics assays have the potential to enable more accurate assessment of PI3K/AKT/PTEN pathway activation in tumor tissues from patients treated with inhibitors of this key pathway. Citation Format: Sahar Ibrahim, Constance A Sobsey, Robert Popp, René P. Zahedi, Gerald Batist, Christoph H. Borchers. Protein quantitation assays for AKT and PTEN to better understand sensitivity and resistance of breast cancer patients to treatment with AKT inhibitor capivasertib [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-20.

Abstract P5-01-20: Blood-based detection of PTEN loss and pathway alterations for personalized treatment of breast cancer

Abstract Introduction: Loss of function of the PTEN tumour suppressor, which leads to elevated PI3K/Akt pathway activation, is one of the common events in breast cancer. Although the mechanisms of PTEN loss of function are diverse, the most frequently observed events are PTEN gene deletion or mutation, resulting in little or no PTEN protein expression measured by tissue-based immunohistochemical staining. Tissue-based immunostaining or genetic analysis could be challenging due to its invasive nature, whereas a robust assay for blood-based detection of copy number loss has been lacking. The aim of this pilot study was to explore the pattern of genetic alterations of PTEN and its downstream PI3K-AKT pathways in breast cancer using a minimally-invasive, blood-based next generation sequencing (NGS) technology. Methods: Plasma samples were prepared from a cohort of 244 breast cancer (BC) samples of all stages. Cell-free DNA (cfDNA) was extracted from plasma sample and further analyzed using the PredicinePLUS™ NGS 180-gene panel. Specifically, cfDNA was enriched for targeted regions using a hybridization-based protocol, and sequenced using Illumina sequencer. Mutational profiling was analyzed using Predicine’s proprietary DeepSea bioinformatics platform with focus on coding exonic regions of genes of interests in PTEN, PI3K and AKT pathway. Results: cfDNA-based PTEN copy number loss was detected in 7/244 BC samples, whereas PTEN mutations were found in 19 out of 244 BC samples leading to loss of PTEN. Specifically, there are frameshift variants (p.Ile8MetfsTer16 and p.Arg130GlnfsTer4), stop gain variant (p.Arg233Ter, p.Glu242Ter), start lost variant (p.Met1?), inframe deletion variants (p.Ile101del), frameshift deletion variant (p.Ile168SerfsTer11), missense variants (p.Cys136Arg, p.Ile122Asn, p.Phe206Leu, p.Pro30Leu, p.Leu318Phe). Along the PI3K-AKT pathway, we also observed activating mutations in AKT1 (E17K only) in 12/244 samples, PIK3CA (p.His1047Arg, p.Glu545Lys, p.Glu542Lys, etc) in 99/244 samples, PIK3CB variants (p.Gly1031Trp, p.Arg153Cys, p.Tyr888Ter, p.Ser890Cys) in 4/244 samples. Interestingly, PTEN loss and PI3K/AKT pathway alterations were not mutually exclusive events in breast cancer. Conclusions: This study demonstrated the capacity of blood-based detection of gene deletion and genomic variants associated with loss of PTEN function in breast cancer. The findings further revealed the mutational spectra of PTEN-PI3K-AKT pathway alterations that could lead to better understanding of the biological mechanisms of PTEN loss in breast cancer. This blood-based liquid biopsy assay may ultimately result in improvement of precision diagnostics for biomarker-driven treatment options and patient prognosis in breast cancer. Citation Format: Pan Du, Eric Jia, Zhixin Zhao. Blood-based detection of PTEN loss and pathway alterations for personalized treatment of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-20.

Abstract P1-19-05: Capivasertib (AZD5363) in combination with fulvestrant in PTEN-mutant ER+ metastatic breast cancer

Abstract Background: Loss of function in the tumor suppressor gene, PTEN, activates PI3K/AKT signaling, driving tumor growth. Somatic mutations in PTEN occur in 5-10% of estrogen-receptor-positive (ER+) breast cancer (BC), and PTEN loss/inactivation is associated with an aggressive BC phenotype and poor outcome. Capivasertib, a pan-AKT kinase inhibitor, has shown antitumor activity in solid tumors. In ER+ BC, suppression of PI3K/AKT signaling results in a compensatory increase in ER-dependent transcription, potentially limiting the efficacy of AKT inhibitors when given as monotherapy. We therefore investigated concurrent inhibition of AKT and ER with combination therapy of capivasertib and fulvestrant in PTEN-mutant ER+ metastatic BC (MBC). Methods: In an expansion cohort (part F) of a Phase I study (NCT01226316), oral capivasertib 400 mg twice daily, 4 days on 3 days off, and fulvestrant at labeled dose, was administered to ER+ MBC patients (pts) with tumors harboring a deleterious PTEN alteration (identified in tissue/plasma by local next-generation sequencing [NGS], with central NGS and immunohistochemistry [IHC] performed retrospectively). Pts were enrolled in fulvestrant-naïve (FN) or fulvestrant-resistant (FR) cohorts (max 24 pts/cohort). Key objectives included safety and efficacy based on 24-week clinical benefit rate (CBR). Results: At data cut-off, 31 pts (12 FN; 19 FR) received treatment. Median number of prior metastatic regimens was 7. FN pts had higher rates of visceral disease (100%) and prior chemotherapy receipt (median 4 [range 0-8]) than FR pts (84%; median 2 [1-7]), respectively]. CBR and median progression-free survival (PFS) were 17% and 2.6 months in FN pts, and 37% and 4.1 months in FR pts, respectively (Table). Twenty-four patients (77%) had PTEN mutations and 7 (23%) had PTEN gene deletions determined by local NGS. Central plasma NGS confirmed 79% (19/24) of the PTEN mutations, and IHC confirmed complete loss of the PTENprotein in 85% (22/26) of cases. Treatment-related grade ≥3 adverse events (AEs) occurred in 32%, most frequently diarrhea and maculopapular rash (both n=2 pts). Treatment-related AEs resulted in dose reduction in 2 pts. Table. Clinical efficacyFN, n=12FR, n=19ORR, % (95% CI)8 (0.2, 39)21 (6, 46)CBR, % (95% CI)17 (2, 48)37 (16, 62)Confirmed response, n (%)1 (8)4 (21)Stable disease ≥24 weeks, n (%)2 (17)3 (16)Median PFS, months (95% CI)2.6 (1.2–4.2)4.1 (1.5–6.7)Median duration of response, months (95% CI)5.5 (NC–NC)6.9 (1.4–NC)Data cut-off was 21 March 2019. Median time from last fulvestrant administration to study entry in FR pts (n=19) was 13.8 months (range 0.7–28.2). CBR was defined as confirmed responders and those with stable disease ≥24 weeks. NC, not calculable (because of limited pt numbers); ORR, objective response rate Conclusions: Capivasertib plus fulvestrant is clinically active in heavily pretreated PTEN-mutated ER+ MBC, including in pts with prior resistance to fulvestrant. Efficacy appeared marginally better in FR than FN pts, possibly due to enrichment of pts with more aggressive disease in the FN cohort. Further analyses of the relationship between genomic features, such as concurrent mutations with drug activity, will be reported. Citation Format: Lillian M Smyth, Gerald Batist, Funda Meric-Bernstam, Peter Kabos, Iben Spanggaard, Ana Lluch, Alison Schram, Andrea Varga, Andrea Wong, Helen Ambrose, Alan Barnicle, T. Hedley Carr, Elza C de Bruin, Carolina Salinas-Souza, Andrew Foxley, Joana Hauser, Justin PO Lindemann, Rhiannon Maudsley, Robert McEwen, Michele Moschetta, Martine Roudier, Gaia Schiavon, Pedram Razavi, Udai Banerji, Sarat Chandarlapaty, José Baselga, David M Hyman. Capivasertib (AZD5363) in combination with fulvestrant in PTEN-mutant ER+ metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-05.

PTEN-deficient cells prefer glutamine for metabolic synthesis

Abstract PTEN loss-of-function mutations frequently occur in gliomas and lead to poor overall survival. PTEN deficiency induces metabolic reprogramming, which may provide therapeutic targets. PTEN is known to impact the Warburg effect and glutaminolysis. To uncover essential glutamine-related metabolic changes specific in PTEN-deficient cells and thus provide potential therapeutic targets, we performed capillary electrophoresis–mass spectrometry-based metabolomics analysis and metabolic flux analysis under different glutamine culture conditions and PTEN alteration status. Glu, Asn, Gly, Ala, and 1-methylnicotinamide were decreased in PTEN-deficient cells under normal culture conditions. Meanwhile, under Gln-deprived culture conditions, Glu, citrate, and UTP synthesis were reduced and acetyl carnitine was increased in PTEN-deficient cells. The reliance on Gln was increased for metabolic intermediates synthesis but decreased for energy production in PTEN-deficient cells. However, the reliance on Gln for UTP synthesis cannot be targeted due to anaplerotic synthesis of UTP from other sources. How to target these metabolic addictions needs further research.

Nab-paclitaxel and Alpelisib for the Treatment of Anthracycline Refractory Triple Negative Breast Cancer With PIK3CA or PTEN Alterations

Nab-paclitaxel and Alpelisib for the Treatment of Anthracycline Refractory Triple Negative Breast Cancer With PIK3CA or PTEN Alterations

Abstract B091: Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV(+) versus HPV(–) forms reveals a different set of potentially actionable biomarkers

Abstract Introduction: One major form of vulvar squamous cell carcinoma (vSCC) is associated with detectable high-risk strains of human papillomavirus (hrHPV) and is often accompanied by usual-type vulvar intraepithelial neoplasia (VIN). The second major form of vSCC is often associated with chronic dystrophic or inflammatory lesions in postmenopausal women, does not harbor detectable HPV infection, and is often preceded by p53-mutant differentiated VIN. While studies have examined the two subtypes, no large-scale genomic study has been performed to our knowledge. We sought to assess the genomics of a large cohort of aggressive vSCCs, with an aim to identify distinct mutational signatures based on the presence or absence of hrHPV genome reads. Methods: 280 vSCC were tested by hybridization capture of up to 406 cancer-related genes evaluated for base substitutions, small indels, amplification (amp), and rearrangements. HPV genome sequences were detected by de novo assembly of non-human sequencing reads and BLASTn comparison against all viral nucleotide sequences in the NCBI RefSeq database. Tumor mutational burden (TMB, mutations/Mb) was determined on ~1.1 Mbp of sequenced DNA. PD-L1 status was determined by IHC (Dako 22C3), with ≥50% tumor proportion score defined as high positive. Results: 102/280 vSCCs contained hrHPV sequences. Of these, 90 were HPV-16, 7 HPV-18, 1 HPV-31, 3 HPV-33, 1 HPV-58, and 1 HPV-67. Patients were significantly younger in the HPV(+) group (median 59 v. 64 years, p=0.001). Compared with the HPV(–) cohort, HPV(+) cases showed significantly more pathogenic genomic alterations (GA) in PIK3CA (31% vs. 17%, p=0.004), PTEN (14% vs. 2%, p<0.0001), EP300 (14% vs. 1%, p<0.0001), STK11 (14% vs. 1%, p<0.0001), AR (5% vs. 0%, p=0.006), and FBXW7 (10% vs. 3%, p=0.03). In contrast, HPV(–) cases showed significantly more alterations in TP53 (82% vs. 3%, p<0.0001), TERTp (71% vs. 8%, p<0.0001), CDKN2A (55% vs. 2%, p<0.0001), CCND1 (23% vs. 2%, p<0.0001), FAT1 (25% vs. 4%, p<0.0001), NOTCH1 (19% vs. 6%, p=0.002), and EGFR (amp: 12% vs. 0%, p<0.0001), as well as a higher rate of 9p24.1 (PDL1/PDL2) amp (7% vs. 1%) and PD-L1 IHC high-positive tumor staining (33% vs. 9%, p=0.04). Differences in alterations were observed between known primary and metastatic sites in cases with similar HPV status but did not reach significance (table). HPV(+)HPV(–) PrimaryMetastasisPrimaryMetastasis # of cases504112442 Age (range)58 (36-81)60 (29-83)64 (25-89)63 (45-89) Median TMB (range)5.2 (0-18.3)6.1 (0-47.8)3.5 (0-90.5)5.0 (0-13) PIK3CA GA26%37%17%17% PTEN GA18%10%2%2% STK11 GA10%22%1%2% FBXW7 GA10%10%5%0% TP53 GA0%5%82%81% TERTp GA6%10%73%64% CDKN2A GA0%5%55%52% CCND1 GA2%2%20%29% EGFR amp0%0%12%14% CD274(PD-L1) amp*0%0%6%10% PD-L1 IHC high*8%11%30%33% TMB >10*6%24%3%19% Conclusions: vSCCs show significant differences in molecular profile based on HPV status. 63% of metastatic HPV(+) cases (54% overall) have a potentially actionable alteration in the PI3K/mTOR pathway, and 42% of metastatic HPV(–) cases (39% overall) have at least one potential predictive biomarker* for response to immunotherapy. Our findings provide compelling rationale for tandem comprehensive genomic profiling and HPV assessment of advanced vulvar SCCs to more fully inform therapeutic options and stratification in clinical trials. Citation Format: Erik A Williams, Adrienne J Werth, Meagan Montesion, Ethan S Sokol, Dean C Pavlick, Nikunj A Shah, Jo-Anne Vergilio, Natalie A Danziger, Jonathan K Killian, Douglas A Lin, Vincent A Miller, Jeffrey S Ross, Julia A Elvin. Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV(+) versus HPV(–) forms reveals a different set of potentially actionable biomarkers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B091. doi:10.1158/1535-7163.TARG-19-B091

Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies.

Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.

Mosaic PTEN alteration in the neural crest during embryogenesis results in multiple nervous system hamartomas

The contribution of mosaic alterations to tumors of the nervous system and to non-malignant neurological diseases has been unmasked thanks to the development of Next Generation Sequencing (NGS) technologies. We report here the case of a young patient without any remarkable familial medical history who was first referred at 7 years of age, for an autism spectrum disorder (ASD) of Asperger type, not associated with macrocephaly. The patient subsequently presented at 10 years of age with multiple nodular lesions located within the trigeminal, facial and acoustic nerve ganglia and at the L3 level. Histological examination of this latter lesion revealed a glioneuronal hamartoma, exhibiting heterogeneous PTEN immunoreactivity, astrocyte and endothelial cell nuclei expressing PTEN, but not ganglion cells. NGS performed on the hamartoma allowed the detection of a PTEN pathogenic variant in 30% of the reads. The presence of this variant in the DNA extracted from blood and buccal swabs in 3.5 and 11% of the NGS reads, respectively, confirmed the mosaic state of the PTEN variant. The anatomical distribution of the lesions suggests that the mutational event affecting PTEN occurred in neural crest progenitors, thus explaining the absence of macrocephaly. This report shows that mosaic alteration of PTEN may result in multiple central and peripheral nervous system hamartomas and that the presence of such alteration should be considered in patients with multiple nervous system masses, even in the absence of cardinal features of PTEN hamartoma tumor syndrome, especially macrocephaly.

Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients

ObjectiveCervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. MethodsDuring 2008–2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. ResultsThe frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild–type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). ConclusionsMore than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.

Abstract GMM-061: MOLECULAR CHARACTERIZATION OF MOUSE MODELS OF HIGH-GRADE SEROUS CARCINOMA ARISING IN THE OVIDUCT

Abstract We recently developed genetically engineered mouse models (GEMMs) of oviductal high-grade serous carcinoma (HGSC) based on conditional inactivation of several different combinations of tumor suppressor genes (Brca1, Trp53, Rb1, and Nf1) that are recurrently mutated in human HGSCs. The histopathological features of the mouse tumors closely mimic their human tumor counterparts. In order to characterize how well the mouse tumors recapitulate the molecular characteristics of human HGSCs, targeted exome sequencing was used to analyze the 32 most commonly mutated genes in human HGSC, in 60 mouse tumors arising in the context of Brca1, Trp53, Rb1, and/or Nf1 inactivation. We employed the sequence data to assess DNA copy number alterations (CNAs) and single nucleotide variants (SNVs) in the mouse tumors. Compared to 14 normal tissues and 8 oviductal tumors arising in the context of Apc, Pten, ± Arid1a inactivation, the mouse HGSCs showed a high level of genomic instability, with many widely distributed CNAs – very similar to the widespread CNAs observed in human HGSCs. Targeted exome sequencing also showed that a subset of the mouse tumors acquired alterations observed in human HGSCs, including amplification of cMyc, and deletion of Pten. Variant analysis identified nonsynonymous SNVs in Csmd3, Crebbp, Pten, Mettl17, and Zymynd8 and a frameshift deletion of Pten. Sanger sequencing confirmed the presence of these somatic mutations in the mouse tumors and their absence in matched normal tissues. Loss of PTEN expression was observed in those tumors that acquired somatic Pten alterations. These data show that HGSCs arising in our GEMMs have very similar molecular characteristics to their human tumor counterparts. The somatic alterations are likely acquired during the relatively lengthy period (several months) between tumor initiation and progression to overt malignancy. These features render the models particularly well suited for studying the early phases of HGSC development and for translational applications aimed at identifying effective strategies for HGSC prevention and early detection. Citation Format: Yali Zhai, Yisheng Wang, Stephanie M. Schulman, Kevin Hu, Albert Liu, Scott A. Tomlins, Eric R. Fearon, and Kathleen R. Cho. MOLECULAR CHARACTERIZATION OF MOUSE MODELS OF HIGH-GRADE SEROUS CARCINOMA ARISING IN THE OVIDUCT [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-061.

PATH-35. RETROSPECTIVE ANALYSIS OF 145 PATIENTS WITH GLIOBLASTOMA; CORRELATING MOLECULAR ALTERATION INCIDENCE WITH DEMOGRAPHICS, TUMOR LOCATION, AND PROGNOSIS

Abstract Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.

CMET-09. A UNIQUE CASE OF PRIMARY GLIOSARCOMA WITH METASTASIS TO SACRUM ON BEVACIZUMAB

Abstract INTRODUCTION Gliosarcoma is a rare variant of glioblastoma that accounts for approximately 0.48% of all adult brain tumors. Although, metastatic potential of gliosarcoma via hematogenous route has been proposed in the past, we report the first case of metastasis to the sacrum while undergoing treatment on bevacizumab. CASE REPORT: A 40-year-old woman presented with acute onset severe headache with pertinent examination findings of left upper extremity pronator drift. Imaging revealed right frontal lobe enhancing mass measuring 4.5 x 3.7 cm associated with edema and 10 mm leftward midline shift. A right frontal craniotomy for tumor debulking showed gliosarcoma (IDH wild-type, WHO grade 4). She was initiated on radiotherapy with concomitant and adjuvant temozolomide via Stupp’s protocol after second debulking surgery. Chemotherapy regimen was changed to bevacizumab when tumor progression was identified. Within six months of initiation of bevacizumab, she developed left leg shooting pain. Imaging revealed heterogeneously enhancing mass in the left hemisacral region measuring 6.2 cm concerning for metastatic process. Sacral bone biopsy showed malignant cells which were negative for an extensive immunohistochemical panel (including GFAP and Olig2), suggesting metastasis of the sarcomatous element of gliosarcoma and arguing against a second malignancy. Next generation sequencing performed on both the intracranial and sacral tumor showed an identical molecular prolife (including PTEN, NF1, TERT and TP53 genomic alterations), confirming common origin. After completion of radiation therapy to sacral region, chemotherapy regimen included lomustine followed by pembrolizumab. The patient died at 14 months after initial presentation due to disease progression. DISCUSSION To the best of our knowledge, this is the first case primary of gliosarcoma with metastases to the sacrum while evolved on chemotherapy with bevacizumab. The aim of this report is to bring awareness to medical community in order to expedite the diagnosis and management.

241P - Impact of genomic alterations and HPV genotypes on clinical outcomes of Japanese patients with locally advanced cervical cancer

BackgroundThe aims of this study were to investigate the genetic alternations of locally advanced cervical cancer and to elucidate the associations among clinico-pathological factors, genomic alterations and clinical outcomes of the patients receiving concurrent chemo-radiotherapy (CCRT). We performed the targeted sequencing for somatic mutations across the hotspot regions of 50 cancer-related genes using biopsy specimens. MethodsSeventy-six patients diagnosed as FIGO Stage III to IVA cervical cancer underwent radiation therapy or CCRT at National Cancer Center Hospital between January 2008 and December 2017. All the patients received external beam radiation therapy and brachytherapy. The most of chemotherapy regimen was cisplatin. Genomic DNAs extracted from formalin-fixed and paraffin-embedded tumor tissues were subjected to the analysis using an Ion AmpliSeq TM Cancer Hotspot Panel v2. Six patients were disqualified from this study because of low quality DNA. Oncogenic or pathogenic variants registered in the OncoKB and the ClinVar databases were defined as mutations. In the present study, gene aberrations with evidence levels 1A-3A were judged as actionable mutation for molecular targeted drugs. HPV infection was detected by in-situ hybridization and genotypes were determined by Sanger sequencing. ResultsSeventy patients were enrolled in this study. Sixty-five patients (93%) had squamous cell carcinoma. Pathogenic mutations were detected in 47 cases (67%); frequencies of gene alterations in PIK3CA (51%), FBXW7 (10%), PTEN (7.1%) and TP53 (5.7%). The clinical factor associated with poor survival was the tumor diameter. Cox regression analysis showed the tumor diameter larger than 70mm were associated with shorter progression-free survival (PFS) (Hazard ratio = 2.96, P = 0.0048) in multivariate analysis. Patients infected without HPV16/18 had poor PFS than those with HPV 16/18 (Log-rank P = 0.025). TP53 mutants were correlated with poor PFS (Log-rank P = 0.044). Thirty-seven patients (53%) have actionable genomic alternations. ConclusionsLarger tumor diameter, non HPV16/18 and TP53 mutants correlated with worse outcomes to CCRT in the Japanese patients with locally advanced cervical cancer. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Toward Systems Pathology for PTEN Diagnostics.

Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.

P2.01-39 Serial Plasma ctDNA Tests Identify Genomic Alterations for Early Prediction of Osimertinib Treatment Outcome in T790M+ NSCLC

Recent advances in detection of genomic DNA from plasma samples allow us to follow the alteration of shedding tumor DNA in plasma before and after systemic treatment with multiple biopsies. Osimertinib is the standard of care for NSCLC patients with T790M mutations. We plan to use serial plasma cfDNA genomic alteration to predict osimertinib efficacy and search for possible resistance mechanisms. We prospectively collected plasma from patients of EGFR mutation-positive NSCLC who harbored acquired EGFR T790M mutation following prior EGFR-TKI therapy. Plasma samples were collected before starting osimertinib treatment, 4 weeks following osimertinib treatment and upon disease progression. ctDNA were detected by Guardant360 gene panel test. Fifteen patients (median age 62 [range 48-77], 53% men, 53% exon 19 deletion and 47% exon 21 L858R mutation) received osimertinib treatment. Acquired T790M mutation was diagnosed by using plasma sample only (Cobas® or digital PCR) (n = 11), tissue or pleural effusion only (n = 2), and both tissue and plasma samples (n = 2). Before starting osimertinib treatment, activating mutations were detected in plasma in all patients, T790M was detected in 93% (n = 14) and TP53 mutation was detected in 47% (n = 7) of the patients by using Guardant360. After osimertinib treatment, 11 out of the 14 patients had non-detectable plasma T790M at the 4th week. Follow-up CT at least 8 weeks following osimertinib treatment of the 11 patients disclosed decreased tumor size (6 confirmed PR, 1 unconfirmed PR and 5 SD by RECIST criteria). The remaining 3 patients who had detectable plasma T790M (n = 2) or increased activating mutation allele frequency (n = 1) at the 4th week had progressive disease within 16 weeks. The first patient had initial PR but later developed C797S on progression. The second patient developed new liver tumor following prior stable disease. This patient had baseline TP53 and CDKN2A mutations detected in the plasma, and allele frequencies decreased at the 4th week and increased on progression. The last patient had rapid progression on osimertinib treatment, and alterations in PTEN and TP53 were detected on baseline and increased at the 4th week and on progression. In that patient, T790M mutation was not detectable at the 4th week but activating mutation increased in allele frequency at the 4th week and on progression. Regarding patients with baseline TP53 mutation, 4 (57%) patients who had non-detectable plasma TP53 mutation at the 4th week achieved disease control, and 2 (29%) patients had detectable or increased TP53 mutation allele frequency had PD within 16 weeks. 4 week plasma ctDNA following osimertinib treatment may predict early progression within 16 weeks.

882P - Activating mutations in AKT1/PIK3CA are associated with poor clinical outcomes in metastatic prostate cancer (mPC)

BackgroundHotspot activating mutations in AKT1 and PIK3CA occur uncommonly in mPC. The incidence and clinical course of patients (pts) with AKT1/PIK3CA hotspot mutations (A/P HSM) is poorly characterised. MethodsWe performed deep targeted sequencing on 1381 cell-free DNA samples from 773 pts with mPC. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), time to PSA progression (TTPP) on first-line metastatic CRPC therapy (1L mCRPCT) and overall survival (OS, defined as time from 1L mCRPCT to death). The control cohort consisted of 196 mCRPC pts with wild-type AKT1/PIK3CA treated with 1L abiraterone + prednisone (ABI) or enzalutamide (ENZ). ResultsTruncal A/P HSM were identified in 5.5% (31/567) of pts with detectable ctDNA, of which p.E17K (n=10) and p.E545K/Q/A (n=12) mutations were most common. When compared to the control cohort, tumors with A/P HSM had a significantly higher rate of TP53 defects (74% vs. 52%, P=0.03), fewer copies of AR (median 4.7 vs. 10.3, P=0.02), but similar PTEN alterations. 27 pts with A/P HSM had evaluable clinical data. At diagnosis, median age was 62.4 y, 66.7% had Gleason score ≥8, 53.8% presented with metastatic disease, and median PSA was 27 (range 6.3 – 9999). 11 pts (40.7%) had ADT plus either docetaxel or enzalutamide in castration-sensitive setting. Comparing the pts with A/P HSM to the control cohort, median time from ADT to CRPC was 11.5 m vs. 17.6 m (HR 1.18, 95% CI 0.78 – 1.79, P=0.46); median OS was 19.6 m vs. 27.3 m (HR 1.71, 95% CI 1.1 to 2.8, P=0.03). 23 pts had ABI or ENZ as 1L mCRPCT. PSA50 was 57% vs. 70% in the control cohort, P=0.19; median TTPP on 1L CRPCT was 5.8 m vs. 8.2 m (HR 1.18, 95% CI 0.7 – 2.0, P=0.54). A pt with an AKT1 p.E17K mutation received ipatasertib as third-line therapy for mCRPC. PSA50 was achieved (baseline PSA 520, nadir PSA 251 ug/L), and TTPP was 5.9 m. ConclusionsOur data shows mPC pts with A/P HSM have significantly worse overall survival, and may have an attenuated response to androgen-axis targeted therapy than AKT1/PIK3CA wild-type pts. This subset of pts may benefit from AKT inhibitor therapy. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureS.Y.F. Fu: Travel / Accommodation / Expenses: Roche. S. Yip: Advisory / Consultancy: Bayer. B. Tran: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen-Cilag; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Tolmar; Advisory / Consultancy: Ipsen. F. Saad: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sanofi. K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: ESSA; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Lily/ImClone; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.

PTEN and Gynecological Cancers.

PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications.