Katharina Leitner

Biopsy‐proven residual cervical cancer at the end of combined chemoradiation predicts poor outcome—Retrospective single‐center cohort study

Abstract Introduction Persistent tumor after combined chemoradiation for locally advanced cervical cancer is an established prognostic factor. Detection may include magnetic resonance imaging, positron emission tomography (PET) combined with CT scan, ultrasound, or biopsies; however, no agreement about the best method and time point has been reached. In our institution, a standardized biopsy protocol of at least four punch biopsies is routinely performed at the last brachytherapy with re‐biopsies 6 weeks later in cases not showing histologic complete response (hCR). This study aims to assess the prognostic relevance of these biopsies, especially with respect to the time point of hCR. Material and Methods This investigation was a retrospective single‐center observational cohort study that included all patients treated for locally advanced or node‐positive cervical cancer with combined chemoradiation at the University Hospital Innsbruck between 2008 and 2023. Patients with a hCR at the end of radiotherapy were classified as primary negative and otherwise as primary positive. Primary positive patients that achieved complete response at a control biopsy 6 weeks later were classified as secondary negative, and the remaining patients with residual tumor as secondary positive. Progression‐free survival (PFS) and overall survival (OS) were compared between all these groups. Results We included 184 patients in this study, from which 46 (25%) were classified as primary positive. These patients experienced a significantly worse PFS compared to primary negative patients ( p  = 0.008, HR = 2.03, 95% CI [1.20, 3.45]). The difference in PFS was also evidenced when comparing primary negative patients to those who had a hCR 6 weeks after radiotherapy (secondary negative) ( p  = 0.018, HR = 2.00, 95% CI [1.13, 3.56]). However, in primary positive patients, OS was not significantly reduced ( p  = 0.29, HR = 1.45, 95% CI [0.73, 2.86]). Conclusions Early response evaluation using punch biopsies at the time of the last brachytherapy can identify patients with residual tumor, which exhibit a statistically significant and clinically meaningful risk of disease progression. This risk was not reversed even in the case of a delayed hCR 6 weeks after completion of chemoradiation.

Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer

Abstract Purpose: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. Experimental Design: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). Results: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33–0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31–0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74–1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07–0.72). Conclusions: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.