Investigator
Leiden University
Response to Systemic Therapies in Patient-Derived Cell Lines from Primary and Recurrent Adult Granulosa Cell Tumors
Abstract In patients with the rare adult-type granulosa cell tumor (aGCT), surgery is the primary treatment for both primary and recurrent disease. In cases of inoperable disease, systematic therapy is administered, but variable response rates and drug resistance complicate predicting the most effective therapy. Drug screen testing on patient-derived cell lines may offer a solution. In a national prospective study on aGCT, fresh tissue was cultured into 2D cell lines, testing 27 clinical and experimental drugs. Dose–response curves and synergy were calculated using GraphPad Prism and CompuSyn software. We established 34 patient-derived cell lines from tissue of 20 patients with aGCT. Of these, seven patients had a primary diagnosis of aGCT and 13 patients had recurrent disease. In eight patients, multiple tumor locations were cultured. On each cell line, 10 monotherapies and 17 combinations of drugs were tested. Carboplatin/gemcitabine showed efficacy and synergy in almost all patient-derived cell lines. Synergy could not be detected in the regular carboplatin/paclitaxel and carboplatin/etoposide combinations. Experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Drug screens on patient-derived tumor cell lines reflect the reality of the variable response of systemic therapy in patients with aGCT. In future research, this technique may be used to personalize the systemic treatment of patients with aGCT in a clinical study. The good response to carboplatin/gemcitabine in our patient-derived cell lines can then be confirmed in a clinical setting.
Clinical and Molecular Characteristics of High-Risk, Recurrent, or Metastatic Endometrial Cancer That Is Human Epidermal Growth Factor Receptor 2–Low
PURPOSE Recent success of human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features. METHODS HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status. RESULTS HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value. CONCLUSION A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.
Response to Nahshon and Lavie
Sexual Health and Quality of Life in Patients With Low-Risk Early-Stage Cervical Cancer: Results From GCIG/CCTG CX.5/SHAPE Trial Comparing Simple Versus Radical Hysterectomy
PURPOSE Simple hysterectomy and pelvic node assessment (SHAPE) is a phase III randomized trial (ClinicalTrials.gov identifier: NCT01658930 ) reporting noninferiority of simple compared with radical hysterectomy for oncologic outcomes in low-risk cervical cancer. This study presents secondary outcomes of sexual health and quality of life (QOL) of the SHAPE trial. METHODS Participants were randomly assigned to receive either radical or simple hysterectomy. Sexual health was assessed up to 36 months postoperatively using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised and QOL using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Cervical Cancer-Specific Module (QLQ-CX24) questionnaires. RESULTS Among participants with at least one QOL measure, clinical and pathologic characteristics were balanced and with no differences in preoperative baseline scores for sexual health or QOL between groups. FSFI total score met the cutoff for dysfunction up to 6 months ( P = .02) in the radical hysterectomy group. Group differences favored simple hysterectomy for FSFI subscales: desire and arousal at 3 months ( P ≤ .001) and pain and lubrication up to 12 months ( P ≤ .018). Both groups met the cutoff for sexual distress but was higher in radical hysterectomy at 3 months ( P = .018). For QLQ-CX24, symptom experience was significantly better up to 24 months ( P = .031) and body image better at 3, 24, and 36 months ( P ≤ .01) for simple hysterectomy. Sexual-vaginal functioning was significantly better up to 24 months ( P ≤ .022) and more sexual activity up to 36 months ( P = .024) in the simple hysterectomy arm. Global health status was significantly higher at 36 months for simple hysterectomy ( P = .025). CONCLUSION Simple hysterectomy was associated with lower rates of sexual dysfunction than radical hysterectomy, with a lower proportion of women having sustained sexual-vaginal dysfunction. These results further support the benefit of surgical de-escalation for low-risk cervical cancer.
Short‐term surgical complications after radical hysterectomy—A nationwide cohort study
AbstractIntroductionCentralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short‐term surgical complications and to evaluate its possible predictors in women with early‐stage cervical cancer.Material and methodsWomen diagnosed with early‐stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications.ResultsA total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73‐6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45‐6.79), vascular disease (OR 1.90; 95% CI 1.07‐3.38), and medical center (OR 2.83; 95% CI 1.18‐6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89‐1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10‐189.12) and body mass index (OR 1.15; 95% CI 1.08‐1.22) were found to be independent predictors of excessive perioperative blood loss.ConclusionsShort‐term surgical complications developed in 35% of the women after radical hysterectomy for early‐stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss.
Radical Versus Simple Hysterectomy and Pelvic Node Dissection With Low-risk Early Stage Cervical Cancer
The reason this study is being done is to see if a simple hysterectomy is as good as a radical hysterectomy in preventing cancer of the cervix from returning, and whether, because less tissue surrounding the uterus is removed during surgery, there are fewer side-effects after the surgery and in the long-term.
