The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

NCT02008734.

Background At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. Materials and methods Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. Results NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). Conclusion NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

No abstract

Background: In this monocentric randomized trial we aimed at identifying if short-term preoperative palbociclib treatment is associated with decreased proliferation and early biomarker changes in patients with early breast cancer (EBC) Methods: Untreated EBC patients were randomized 3:1 to oral palbociclib 125mg daily for 14 days until the day before the surgery vs no treatment. FFPE and frozen samples were extracted at baseline and at surgery. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Immunostaining (Ki67, RB, pRB, p16, pAKT, pER), FISH (CCND1) and gene expression (GE) arrays were performed pre- and post-treatment. PIK3CA and AKT1 mutations were assessed pretreatment. Results: 74 patients were randomized in the palbociclib arm and 26 in the control arm. 93% tumors were HR-positive; 8% HER2-positive. Palbociclib treatment led to significantly more patients with antiproliferative response as compared to control (58% vs 10%, p = 0.0003). In addition, mean decrease from baseline in ln(Ki67) was significantly higher at day 15 in the palbociclib arm (p<0.0001). In patients with HR+/Her2-, palbociclib decreased Ki67 in 72% of the patients (vs 5% in control). No Ki67 response was observed in TNBC or Her2-positive tumors (interaction test, p = 0.0038). Palbociclib significantly decreased p-Rb as compared to control (p = 0.0027, ANCOVA model). Baseline Rb (interaction test, p = 0.36), pRb (p = 0.89) and p16 (p = 0.13) did not predict palbocicilb effect on Ki67. Palbociclib effect in ki67 correlated with changes in pRB from baseline (Spearman rank correlation r = 0.42, p<0.0001). Additional analyses are ongoing (CCND1 amplification, GE, pAKT, pER, PIK3CA, AKT1) Conclusions: Short-term pre-operative Palbociclib treatment in EBC patients significantly decreased Ki67. This effect depended on molecular subtypes and correlated with changes in pRB, suggesting that bioactivity of palbociclib could be the main determinant of his short term effect on proliferation. Mechanisms of tumor adaptation to CDK4/6 inhibitors (GE, pAKT, pER) are being investigated and will be presented. Citation Format: Monica Arnedos, Bianca Cheaib, Mohamed Amine Bayar, Stefan Michiels, Veronique Scott, Julien Adam, Valerie Leroux-Kozal, Virginie Marty, Chafika Mazouni, Benjamin Sarfati, Ivan Bieche, David Gentien, Suzette Delaloge, Magali Lacroix-Triki, Fabrice Andre. Anti-proliferative response and predictive biomarkers to palbociclib in early breast cancer: The Preoperative Palbociclib (POP) randomized trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT041.

Background: The role of immunotherapy in HR+/HER2-breast cancer is underexplored. The GIADA trial (EUDRACT 2016-004665-10) is a phase II study of neoadjuvant chemotherapy, nivolumab and endocrine therapy for Luminal B breast cancer patients.

Background: CDK4/6 inhibitors have been approved in the recent years for the treatment of advanced hormone receptor-positive breast cancer. For patients with resistance to previous endocrine therapy, the approval is based on the results of the PALOMA-3 trial testing palbociclib in addition to fulvestrant observing a progression-free survival (PFS) of 9.2 months. Nevertheless, in this study no previous treatment with fulvestrant was allowed and no information had been reported of efficacy after everolimus administration. Patients and methods: We collected information from patients treated with palbociclib + fulvestrant in the context of a French compassionate access. We aimed at determining the benefit of this treatment in a real population to provide information about PFS in non-selected patients as well as efficacy of palbociclib and fulvestrant in patients previously treated with fulvestrant and/or everolimus. Median PFS were assessed by Kaplan-Meier survival analysis and compared with log-rank test. Results: 206 patients were identified from 5 institutions. Mean age at treatment was 61 years (range 28 – 85). 55% presented with visceral disease. Lines at where palbociclib + fulvestrant treatment was administered were as follows: 1% 1st line, 8.3% 2nd line, 19.4% 3rd line, 13.6% 4th line, 10.2% 5th lignes and the remaining 47.6% had received ≥6 lines (median: 5 lines, range 1 to 15). A total of 48% patients had previously been treated with fulvestrant. In a subsample of patient where the information was available (n=146), 67.8% patients had received everolimus in combination with endocrine therapy before palbociclib administration. A total of 77 patients were still on treatment. Median PFS on fulvestrant-palbociclib treatment at the date of data cut-off was of 5.46 months (95% CI; 4.6 to 6.6 months). In a univariate analysis, there were no significant differences in median PFS for patients treated or not with previous fulvestrant, suggesting a potential effect of palbociclib to recover sensitivity to fulvestrant (4.7 months for previous fulvestrant treatment [95% CI 4.07 - 6.3 months] vs 6.1 months for no previous fulvestrant [95% CI; 6.3 - 8.02 months], p=0.3559). Similarly, in the subsample of n=146 patients where information about previous everolimus treatment was available at data cut-off, benefit from palbociclib-fulvestrant was not affected by previous everolimus treatment (median PFS 4.8 months for previously treated [95% CI; 4.01 -7.8 months] vs 5.4 months for the untreated everolimus group [95% CI; 4.07 - 9.59 months], p=0.374). Conclusions: Fulvestrant-palbociclib in the real life is associated with a median PFS of 5.5 months, which is below the results provided in the PALOMA-3 trial, reflecting a much more advanced population. Importantly, neither previous everolimus treatment nor fulvestrant therapy affected benefit from fulvestrant-palbociclib in this population in univariate analyses suggesting a potential recovery of fulvestrant sensitivity with CDK4/6 inhibition. Results from multivariate analyses and more detailed information about patients' characteristics and benefit from previous therapies will be provided. Citation Format: Arnedos M, Rusquec P, Morelle M, Lebreton C, Jacquet E, Emile G, Aires J, Debled M, Frenel J-S, Augereau P, Cheaib B, Levy C, Bachelot T. Benefit from palbociclib and fulvestrant based on previous fulvestrant and/or everolimus treatment. Based on a cohort of over 200 patients treated in a French compassionate program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-11.