Salvatore Lopez

Fertility-sparing approach in endometrioid grade II endometrial cancer: the role of molecular classification

To investigate whether molecular classification could support individualized selection of patients with grade II endometrioid endometrial cancer for fertility-sparing approaches. This is a retrospective multi-institutional study. Data of patients undergoing fertility-sparing treatment with a levonorgestrel intrauterine device (with or without oral hormonal therapy) were retrieved. Surrogate molecular classification was used to categorize patients into 4 classes: (1) POLE-mutated, (2) mismatch repair deficient/microsatellite instability high, (3) p53 abnormal, and (4) no specific molecular profile. Overall, data from 23 patients with grade II endometrioid endometrial cancer starting a fertility-sparing attempt were retrieved. The median patient age was 36 (range; 30-41) years. All patients underwent hysteroscopic-guided endometrial biopsies. Hysteroscopic resection of the tumor was performed in 9 (39.1%) patients. According to surrogate molecular classification, 1 (4.3%), 2 (8.7%), 3 (13.1%), and 17 (73.9%) patients were classified as POLE-mutated, p53 abnormal, mismatch repair deficient/microsatellite instability high, and no specific molecular profile, respectively. Molecular classification was not associated with 6-month response rates (p = .080) nor with best response rates (p = .366). Overall, 7 women attempted to achieve a pregnancy; 3 underwent in vitro fertilization. Three patients achieved a pregnancy (1 first-trimester miscarriage and 2 term live births). A total of 10 (43.4%) patients were diagnosed with progressive disease during hysteroscopic surveillance. Overall, 19 (82.6%) patients required hysterectomy. Three (13%) patients required adjuvant therapy for the presence of locally advanced disease (1 stage II, and 2 stage III). Over a median (range) follow-up of 28.7(8.2-91.1) months, no recurrence or disease-related death occurred. Less than 10% of women with grade II endometrioid endometrial cancer starting a fertility-sparing attempt achieve a term pregnancy. In our series, molecular classification did not influence response rate. Further collaborative registers are needed.

Age-specific predictors of cervical dysplasia recurrence after primary conization: analysis of 3,212 women

This study aimed to identify predictors of recurrence/persistence of cervical intraepithelial neoplasia grade 2+ (CIN2+) lesion (r-CIN2+) after primary conization. Retrospective analysis involving all consecutive women having conization for CIN2+ between 1998 and 2018. The risk of r-CIN2+ was assessed using Kaplan-Meier and Cox models. Data of 3,212 women were retrospectively identified. After a mean follow-up of 47 (±22.2) months, 112 (3.5%) patients developed r-CIN2+. Mean time interval between prior conization and diagnosis of r-CIN2+ was 26.2 (±13.2) months. Via multivariate analysis, presence of high-risk human papillomavirus (HPV) types at the time of CIN2+ diagnosis, hazard ratio (HR)=3.40 (95% confidence interval [CI]=1.66-6.95) for HPV16/18 and HR=2.59 (95% CI=1.21-5.55) for HPV types other than 16/18, positive margins at primary conization, HR=4.11 (95% CI=2.04-8.26) and HPV persistence after conization, HR=16.69 (95% CI=8.20-33.9), correlated with r-CIN2+, independently. Considering age-specific HPV types distribution, we observed that HPV16/18 infection correlated to an increased risk of r-CIN2+ only in young women (aged ≤25 years; p=0.031, log-rank test); while in the older population (>25 years) HPV type(s) involved had not impact on r-CIN2+ risk (p>0.200, log-rank test). HPV persistence is the main factor predicting r-CIN2+. Infection from HPV16/18 has a detrimental effect in young women, thus highlighting the need of implementing vaccination against HPV in this population. Further prospective studies are warranted for tailoring clinical decision-making for post-conization follow-up on the basis of risk factors.

Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

AbstractHuman trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with IC50 values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.