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OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.
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Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Ftalazinas , Piperazinas , Quinazolinas , Humanos , Femenino , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Recombinación Homóloga , Supervivencia sin Progresión , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , IndolesRESUMEN
PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.
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Gemcitabina , Isoxazoles , Neoplasias Ováricas , Pirazinas , Humanos , Femenino , Desoxicitidina/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Proteínas de la Ataxia Telangiectasia Mutada/genéticaRESUMEN
PURPOSE: To guide the vaccination of adults with solid tumors or hematologic malignancies. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and nonrandomized studies on the efficacy and safety of vaccines used by adults with cancer or their household contacts. This review builds on a 2013 guideline by the Infectious Disease Society of America. PubMed and the Cochrane Library were searched from January 1, 2013, to February 16, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: A total of 102 publications were included in the systematic review: 24 systematic reviews, 14 RCTs, and 64 nonrandomized studies. The largest body of evidence addressed COVID-19 vaccines. RECOMMENDATIONS: The goal of vaccination is to limit the severity of infection and prevent infection where feasible. Optimizing vaccination status should be considered a key element in the care of patients with cancer. This approach includes the documentation of vaccination status at the time of the first patient visit; timely provision of recommended vaccines; and appropriate revaccination after hematopoietic stem-cell transplantation, chimeric antigen receptor T-cell therapy, or B-cell-depleting therapy. Active interaction and coordination among healthcare providers, including primary care practitioners, pharmacists, and nursing team members, are needed. Vaccination of household contacts will enhance protection for patients with cancer. Some vaccination and revaccination plans for patients with cancer may be affected by the underlying immune status and the anticancer therapy received. As a result, vaccine strategies may differ from the vaccine recommendations for the general healthy adult population vaccine.Additional information is available at www.asco.org/supportive-care-guidelines.
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Vacunas contra la COVID-19 , COVID-19 , Neoplasias , Vacunación , Humanos , Neoplasias/terapia , Vacunación/normas , Adulto , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , SARS-CoV-2/inmunologíaRESUMEN
Although cure rates remain low and effective screening strategies are elusive, the recent advances in systemic therapies over the past year highlighted in this review have prolonged survival for women with ovarian cancer. In 2022, the first antibody-drug conjugate for platinum-resistant ovarian cancer received accelerated US Food and Drug Administration (FDA) approval. Confirmatory studies examining the efficacy of mirvetuximab and other antibody-drug conjugates are underway. In the upfront setting, the first data establishing an overall survival benefit from poly(ADP-ribose) polymerase inhibitor maintenance was demonstrated after a 7-year follow-up period. In contrast, long-term updates from poly(ADP-ribose) polymerase inhibitor trials in the noncurative setting reported survival detriments, and the FDA withdrew the respective indications. Several trials attempted to improve upon the standard of care for platinum-sensitive ovarian carcinoma and those with rare ovarian cancer histologies (carcinosarcoma, clear cell carcinoma) but failed to demonstrate a clinically or statistically meaningful benefit. This leaves the open question of how to further optimize systemic therapy for advanced ovarian carcinoma to improve long-term survival and cure rates.
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Antineoplásicos , Inmunoconjugados , Neoplasias Ováricas , Femenino , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Recurrencia Local de Neoplasia/patologíaRESUMEN
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Consenso , Neoplasias Intestinales/tratamiento farmacológico , National Cancer Institute (U.S.) , Tumores Neuroendocrinos/patología , Octreótido/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Estados Unidos , Ensayos Clínicos como AsuntoRESUMEN
PURPOSE: Despite therapeutic advances in the treatment of ovarian cancer (OC), 5-year survival remains low, and patients eventually die from recurrent, chemotherapy-resistant disease. The National Cancer Gynecologic Cancer Steering Committee identified the integration of scientifically defined subgroups as a top strategic priority in clinical trial planning. METHODS: A group of experts was convened to review the scientific literature in OC to identify validated predictive biomarkers that could inform patient selection and treatment stratification. Here, we report on these findings and their potential for use in future clinical trial design on the basis of hierarchal evidence grading. RESULTS: The biomarkers were classified on the basis of mechanistic targeting, including DNA repair and replication stress, immunotherapy and tumor microenvironment, oncogenic signaling, and angiogenesis. Currently, BRCA mutations and homologous recombination deficiency to predict poly (ADP-ribose) polymerase inhibitor response are supported in OC by the highest level of evidence. Additional biomarkers of response to agents targeting the pathways above have been identified but require prospective validation. CONCLUSION: Although a number of biomarkers of response to various agents in OC have been described in the literature, high-level evidence for the majority is lacking. This report highlights the unmet need for identification and validation of predictive biomarkers to guide therapy and future trial design in OC.
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Biomarcadores , Ensayos Clínicos como Asunto , Neoplasias Ováricas , Femenino , Humanos , Adenosina Difosfato/uso terapéutico , Antineoplásicos/farmacología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , National Cancer Institute (U.S.) , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ribosa/uso terapéutico , Microambiente Tumoral , Estados UnidosRESUMEN
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
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Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.
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Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Consenso , Femenino , Predicción , Humanos , Neoplasias Ováricas/terapiaRESUMEN
This commentary complements the report from Nixon and colleagues by addressing the critical definitions, assay and analytical quality control and interpretation, and resources available to advance similar fit-for-purpose biomarker development. See related articles by Nixon et al., p. 2771 and 2779.
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Carcinoma de Células Renales , Neoplasias Renales , Bevacizumab , Biomarcadores , Humanos , Control de CalidadRESUMEN
PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.
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Neoplasias Ováricas , Platino (Metal) , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Femenino , Humanos , Indoles , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/efectos adversos , Piperazinas , Platino (Metal)/uso terapéutico , QuinazolinasRESUMEN
Importance: Neuroendocrine neoplasms (NENs) have historically been grouped homogenously in clinical trials, despite their heterogeneity. Given the adoption of a more advanced pathologic classification system and drug licensure of several targeted therapies over the last decade, information is needed on whether study characteristics of NEN studies have evolved. Objective: To assess changes in study design, eligibility, accrual, sponsorship, and outcomes between phase II or III NEN clinical trials that began enrollment from 2000 to 2009 vs 2010 to 2020. Design, Setting, and Participants: This quality improvement study used a systematic survey of completed studies published between January 1, 2000, and December 31, 2020. Therapeutic phase II and III NEN studies were identified through a database search of Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (EBSCOhost), Web of Science (Clarivate), Cochrane Database of Systematic Reviews (Wiley), ClinicalTrials.gov (National Institutes of Health), EU Clinical Trials Register, and National Cancer Institute Clinical Trials. Data were analyzed between March and June 2021. Main Outcomes and Measures: Study characteristic proportions between the 2 enrollment periods. Results: Of 3243 identified studies, 119 studies met criteria for inclusion, of which 117 studies (54 studies that began enrollment between 2000-2009 and 63 studies that began enrollment between 2010-2020) included exact dates of enrollment and were compared. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were less likely to include all NENs (13 studies [21%] vs 34 studies [63%]; P < .001) and more likely to include select NENs (eg, gastrointestinal neuroendocrine tumors, 25 studies [40%] vs 11 studies [20%]; P = .02; pancreatic neuroendocrine tumors, 32 studies [51%] vs 16 studies [30%]; P = .02). Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to specify tumor differentiation (59 studies [98%] vs 34 studies [63%]; P < .001) or Ki-67 index (23 studies [38%] vs 5 studies [9%]; P < .001) in inclusion criteria. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to use progression-free survival (22 studies [35%] vs 9 studies [18%]; P = .04) rather than objective response rate (19 studies [30%] vs 27 studies [53%]; P = .01) as a primary or coprimary end point. Conclusions and Relevance: These findings suggest that NEN trials enrolling over the last decade were more focused on select tumor populations, compared with studies that began enrollment before 2010. Despite this shift, more than 20% of studies still included all NENs. Studying novel agents in specific disease populations may enhance drug development in the field.
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Ensayos Clínicos como Asunto , Determinación de la Elegibilidad , Tumores Neuroendocrinos , Proyectos de Investigación , Humanos , Evaluación de Resultado en la Atención de Salud , Encuestas y Cuestionarios , Estados UnidosRESUMEN
In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Replicación del ADN/genética , Desoxicitidina/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor/genética , Desoxicitidina/uso terapéutico , Femenino , Humanos , Isoxazoles/uso terapéutico , Mutación , Oncogenes/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Supervivencia sin Progresión , Pirazinas/uso terapéutico , Reparación del ADN por Recombinación/genética , Proteínas de Unión a Retinoblastoma/genética , GemcitabinaRESUMEN
PURPOSE: To provide expert guidance to clinicians and policymakers in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer. METHODS: A multidisciplinary, multinational ASCO Expert Panel reviewed existing guidelines, conducted a modified ADAPTE process, and conducted a formal consensus process with additional experts. RESULTS: Existing sets of guidelines from eight guideline developers were found and reviewed for resource-constrained settings; adapted recommendations from nine guidelines form the evidence base, informing two rounds of formal consensus; and all recommendations received ≥ 75% agreement. RECOMMENDATIONS: Evaluation of adult symptomatic women in all settings includes symptom assessment, family history, and ultrasound and cancer antigen 125 serum tumor marker levels where feasible. In limited and enhanced settings, additional imaging may be requested. Diagnosis, staging, and/or treatment involves surgery. Presurgical workup of every suspected ovarian cancer requires a metastatic workup. Only trained clinicians with logistical support should perform surgical staging; treatment requires histologic confirmation; surgical goal is staging disease and performing complete cytoreduction to no gross residual disease. In first-line therapy, platinum-based chemotherapy is recommended; in advanced stages, patients may receive neoadjuvant chemotherapy. After neoadjuvant chemotherapy, all patients should be evaluated for interval debulking surgery. Targeted therapy is not recommended in basic or limited settings. Specialized interventions are resource-dependent, for example, laparoscopy, fertility-sparing surgery, genetic testing, and targeted therapy. Multidisciplinary cancer care and palliative care should be offered.Additional information can be found at www.asco.org/resource-stratified-guidelines. It is ASCO's view that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.
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Neoplasias Ováricas , Adulto , Antígeno Ca-125 , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/terapia , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Terapia Neoadyuvante , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapiaRESUMEN
PURPOSE: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. PATIENTS AND METHODS: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21-24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. RESULTS: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). CONCLUSIONS: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.
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Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Endometriales/terapia , Histerectomía , Acetato de Medroxiprogesterona/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/administración & dosificación , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/etiología , Femenino , Humanos , Histerectomía/métodos , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/efectos adversos , Persona de Mediana Edad , Piridinas/administración & dosificación , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
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Neoplasias/tratamiento farmacológico , Neoplasias/genética , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , National Cancer Institute (U.S.) , Neoplasias/epidemiología , Neoplasias/patología , Proyectos Piloto , Medicina de Precisión , Estudios Retrospectivos , Análisis de Secuencia de ARN , Estados Unidos/epidemiología , Secuenciación del ExomaRESUMEN
A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Redes Reguladoras de Genes , Variación Genética , Genómica/métodos , Neoplasias/tratamiento farmacológico , Biopsia , Epigénesis Genética , Femenino , Humanos , Masculino , Neoplasias/genética , Neoplasias/patología , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Microambiente TumoralRESUMEN
OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Sorafenib/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Interleucina-8/sangre , Interleucina-8/inmunología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sorafenib/efectos adversosRESUMEN
PURPOSE: To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC). METHODS: Randomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking. RESULTS: The systematic review identified 17 eligible trials. RECOMMENDATIONS: The guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 (g/sBRCA1) or BRCA2 (g/sBRCA2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/sBRCA1/2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of BRCA mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/sBRCA1/2, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed.Additional information is available at www.asco.org/gynecologic-cancer-guidelines.