Uterine leiomyosarcoma.

Uterine leiomyosarcoma is a rare and heterogeneous gynecological malignancy that poses a significant clinical challenge due to its aggressive nature and limited treatment options. Its multifactorial etiopathogenesis involves complex cytogenetic and molecular aberrations, including TP53, RB1, and chromothripsis-associated gene alterations. The non-specific clinical presentation, resembling other benign conditions, complicates early and accurate diagnosis, alongside intricate radiological and pathological patterns.

Primary Analysis of EPIK-O/ENGOT-ov61: Alpelisib Plus Olaparib Versus Chemotherapy in Platinum-Resistant or Platinum-Refractory High-Grade Serous Ovarian Cancer Without Mutation.

Purpose: Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients.

Patients And Methods: EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m once weekly or pegylated liposomal doxorubicin 40-50 mg/m once every 28 days).

LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.

Purpose: To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity.

Patients And Methods: This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in , , , , and (cohort A) or , , , , and (cohort B). The primary end point was overall response rate (ORR) in cohort A.

A phase 2 trial of niraparib plus bevacizumab maintenance therapy following first-line platinum-based chemotherapy with bevacizumab in advanced ovarian cancer: final analysis and overall survival results from OVARIO.

Objective: To report long-term outcomes from the OVARIO trial of niraparib plus bevacizumab maintenance following first-line platinum-based chemotherapy with bevacizumab in advanced ovarian cancer.

Methods: The phase 2, single-arm, open-label trial enrolled adult patients with stage IIIB-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have attempted debulking surgery and have a complete or partial response or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab.

Pembrolizumab plus chemotherapy with or without bevacizumab in East Asian participants with persistent, recurrent, or metastatic cervical cancer: results from KEYNOTE-826 final analysis.

Objective: In the phase 3 KEYNOTE-826 study (NCT03635567), pembrolizumab plus chemotherapy with or without bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) in participants with persistent, recurrent, or metastatic cervical cancer. We report an exploratory analysis of outcomes for participants enrolled in East Asia based on the final analysis of KEYNOTE-826.

Methods: Participants were randomized 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles.

Ultrasensitive detection and tracking of circulating tumor DNA to predict relapse and survival in patients with locally advanced cervical cancer: phase III CALLA trial analyses.

Background: After chemoradiotherapy (CRT), 30%-50% of patients with locally advanced cervical cancer (LACC) relapse, highlighting the unmet need for prognostic biomarkers. In the global randomized CALLA trial (NCT03830866), the addition of durvalumab during and after CRT did not significantly improve progression-free survival (PFS) in a biomarker-unselected intent-to-treat population. We analyzed the association of ultrasensitive circulating tumor DNA (ctDNA) and circulating human papillomavirus (cHPV) DNA detection with relapse and survival in the largest dataset in LACC to date.

Repurposing Food and Drug Administration-approved cancer therapies: exploring endocrine and targeted pathways in low-grade serous ovarian cancer treatment.

Low-grade serous ovarian cancer is a rare epithelial ovarian cancer with limited responsiveness to conventional chemotherapy, particularly, in advanced or recurrent settings. Low-grade serous ovarian cancer is characterized by an indolent growth pattern and a high prevalence of mitogen-activated protein kinase pathway alterations (KRAS, BRAF, NRAS) and hormone receptor positivity, highlighting the potential for targeted therapies. MEK inhibitors (eg, trametinib, binimetinib) specifically target the mitogen-activated protein kinase pathway, whereas endocrine therapies and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors exploit hormone-driven pathways.

Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): an open-label, randomised, controlled, phase 3 trial.

Background: Relacorilant, a first-in-class selective glucocorticoid receptor antagonist, increases a tumour's sensitivity to chemotherapy by reducing cortisol signalling. This study aimed to show whether the addition of relacorilant to nab-paclitaxel improves progression-free and overall survival in females with platinum-resistant ovarian cancer.

Methods: This randomised, controlled, open-label phase 3 trial (ROSELLA [GOG-3073/ENGOT-ov72]) was done at 117 hospitals and community oncology treatment centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea.

Clinical factors influencing retreatment with anti-PD-(L)1 therapies after treatment in early-stage cancers: a modified Delphi consensus study.

Anti-programmed death (ligand) 1 (anti-PD-(L)1) therapies were first introduced in the metastatic setting and have since been approved and reimbursed for treating early-stage cancers in the adjuvant, perioperative, and neoadjuvant settings in many cancer types. Current evidence supporting anti-PD(L)-1 retreatment after relapse with prior neoadjuvant and/or adjuvant anti-PD(L)1 therapy is limited and inconclusive. There is no guidance for clinicians on how and when to retreat with anti-PD-(L)1 therapies when anti-PD-(L)1 therapy was administered in the neoadjuvant and/or adjuvant setting.

Optimal bevacizumab treatment strategy in advanced ovarian cancer: A review.

Bevacizumab was the first targeted therapy developed for newly diagnosed and recurrent advanced ovarian cancer (AOC). Although bevacizumab has been approved for the treatment of AOC for several years, identifying patients who may benefit most from this treatment is still debated. Bevacizumab has been associated with improved progression-free survival (PFS) regardless of clinical risk, but in some countries the use of bevacizumab in the treatment of newly diagnosed AOC has been restricted to higher-risk patients (stage III inoperable or suboptimally debulked disease, or stage IV disease); this is primarily due to the findings of exploratory subgroup analyses from phase III trials that suggest only higher-risk patients derive an overall survival (OS) advantage with bevacizumab.

ENGOT-OV16/NOVA trial of niraparib in recurrent ovarian cancer: Survival and long-term safety.

Objective: To evaluate secondary efficacy endpoints and safety for the ENGOT-OV16/NOVA (NCT01847274) trial of niraparib maintenance therapy after extended follow-up and vital-status-data retrieval. Previously reported analyses (data cutoff, October 1, 2020) indicated benefit of niraparib maintenance therapy beyond first progression, but overall survival (OS) analyses were limited by missing data.

Methods: Patients were randomized 2:1 to niraparib (300 mg once daily) or placebo.

Spontaneous Subdural Hematomas as Initial Presentation of Acquired Coagulopathy: A Case Report.

The evaluation of coagulopathies can be challenging due to the extensive variety of etiologies. This can be particularly complicated in patients with concomitant autoimmune disorders. In this case, a 64-year-old woman presented with intractable headaches and neck pain for two weeks.

Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial.

Background: Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT.

Evaluation of physical function and quality of life before and after nonradical surgical therapy for stage IA1 and IA2-IB1 cervical cancer (GOG-0278).

Objective: To examine patient outcomes before and after cone biopsy (CB) or simple hysterectomy (SH) and pelvic lymph node dissection (PLND) for bladder, bowel, and sexual function, quality of life (QOL), cancer worry, reproductive concerns, and lymphedema.

Methods: We stratified women with stage IA1 (lymphovascular space invasion-positive) and IA2-IB1 (≤2 cm) cervical carcinoma by fertility preservation (CB) or none (SH) with PLND. All patients completed study questionnaires at baseline (preoperatively) and postoperatively at 4-6 weeks and 6-, 12-, 18-, and 24-months, consisting of: Functional Assessment Cancer Therapy - Cervical Cancer (FACT-Cx); Female Sexual Functioning Index (FSFI), and 2 Patient-Reported Outcomes Measurement Information System (PROMIS) items; Gynecologic Cancer Lymphedema Questionnaire (GCLQ); Impact of Events Scale (IES); and Reproductive Concerns Scale (RCS).

Evaluation of efficacy and fertility after nonradical surgical therapy (extra fascial hysterectomy or cone biopsy, with pelvic lymphadenectomy) for stage IA1, IA2, and IB1 cervical cancer (GOG-0278).

Objective: To estimate the efficacy and perioperative morbidity of nonradical surgery (simple hysterectomy [SH] or cone biopsy [CB] plus pelvic lymphadenectomy [PLND] and to report pregnancy outcomes after CB.

Methods: Prospective international study with 3-year follow-up of patients with stage IA1 (lymphovascular space invasion-positive) to IB1 (≤2 cm) cervical cancer stratified by fertility preservation (CB) or none (SH) (both with PLND). Criteria included ≤10 mm stromal invasion and negative margins on loop electrosurgical excision procedure or CB.

Tumor Treating Fields therapy in platinum-resistant ovarian cancer: Results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study.

Purpose: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC).

Patients And Methods: Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m weekly) or PTX.

Characterization of Plasma Cell-Free DNA Variants as of Tumor or Clonal Hematopoiesis Origin in 16,812 Advanced Cancer Patients.

Purpose: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based comprehensive genomic profiling. However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.

Experimental Design: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole-exome and whole-transcriptome next-generation sequencing workflow that independently sequences both plasma-derived cell-free total nucleic acids and the white blood cell DNA and RNA from the buffy coat.

Racial and ethnic enrollment disparities in clinical trials leading to Food and Drug Administration approvals for gynecologic malignancies.

Background: Compared to White women, Black women and other minority groups have a higher age-adjusted incidence risk of cervical and endometrial cancer. However, the extent of racial and ethnic disparities in clinical trial enrollment among studies performed mainly in North America and Europe for gynecologic malignancy is unknown.

Objective: This study analyzed enrollment rates by race/ethnicity in trials that led to Food and Drug Administration approvals for gynecological cancers from 2010 to 2024.

Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated.

Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial.

Aim: Cemiplimab has demonstrated significantly longer survival than physician's choice of chemotherapy in patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. We report the final survival analysis from the phase III randomized study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9).

Methods: Cemiplimab (n = 304) or chemotherapy (n = 304) were administered every 3 weeks.

Incorporating immune checkpoint inhibitors in epithelial ovarian cancer.

Objective: Therapeutic interventions for epithelial ovarian cancer (EOC) have increased greatly over the last decade but improvements outside of biomarker selected therapies have been limited. There remains a pressing need for more effective treatment options that can prolong survival and enhance the quality of life of patients with EOC. In contrast to the significant benefits of immunotherapy with immune checkpoint inhibitors (CPI) seen in many solid tumors, initial experience in EOC suggests limited efficacy of CPIs monotherapy.

Treatment advances across the cervical cancer spectrum.

Cervical cancer is preventable with screening and vaccination approaches; however, access to these preventative measures is limited both nationally and globally and thus many women will still develop cervical cancer. Novel treatments and practice-changing research have improved cervical cancer outcomes over the past few decades. In this Review, we discuss clinical trials that have refined or redefined the treatment of cervical cancers across the early stage, locally advanced, persistent, recurrent and/or metastatic disease settings.