Performance of a targeted methylation-based multi-cancer early detection test by race and ethnicity.

Disparities in cancer screening and outcomes based on factors such as sex, socioeconomic status, and race and ethnicity in the United States are well documented. A blood-based multi-cancer early detection (MCED) test that detects a shared cancer signal across multiple cancer types and also predicts the cancer signal origin was developed and validated in the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978). CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall N = 15,254). In this pre-specified, exploratory, descriptive analysis, test performance was evaluated among racial and ethnic groups. Overall, 4077 participants comprised the independent validation set with confirmed cancer status (cancer: n = 2823; non-cancer: n = 1254). Participants were stratified into the following racial/ethnic groups: Black (non-Hispanic), Hispanic (all races), Other (non-Hispanic), Other/unknown and White (non-Hispanic). Cancer and non-cancer participants were predominantly White (n = 2316, 82.0% and n = 996, 79.4%, respectively). Across groups, specificity for cancer signal detection ranged from 98.1% [n = 103; 95% CI: 93.2-99.5%] to 100% [n = 85; 95% CI: 95.7-100.0%]. The sensitivity for cancer signal detection across groups ranged from 43.9% [n = 57; 95% CI: 31.8-56.7%] to 63.0% [n = 192; 95% CI: 56.0-69.5%] and generally increased with clinical stage. The MCED test had consistently high specificity and similar sensitivity across racial and ethnic groups, though results are limited by sample size for some groups. Results support the broad applicability of this MCED test and clinical implementation on a population scale as a complement to standard screening.

Multi-cancer early detection test sensitivity for cancers with and without current population-level screening options.

There are four solid tumors with common screening options in the average-risk population aged 21 to 75 years (breast, cervical, colorectal, and, based on personalized risk assessment, prostate), but many cancers lack recommended population screening and are often detected at advanced stages when mortality is high. Blood-based multi-cancer early detection tests have the potential to improve cancer mortality through additional population screening. Reported here is a post-hoc analysis from the third Circulating Cell-free Genome Atlas substudy to examine multi-cancer early detection test performance in solid tumors with and without population screening recommendations and in hematologic malignancies. Participants with cancer in the third Circulating Cell-free Genome Atlas substudy analysis were split into three subgroups: solid screened tumors (breast, cervical, colorectal, prostate), solid unscreened tumors, and hematologic malignancies. In this post hoc analysis, sensitivity is reported for each subgroup across all ages and those aged ⩾50 years overall, by cancer, and by clinical cancer stage. Aggregate sensitivity in the solid screened, solid unscreened, and hematologic malignancy subgroups was 34%, 66%, and 55% across all cancer stages, respectively; restricting to participants aged ⩾50 years showed similar aggregate sensitivity. Aggregate sensitivity was 27%, 53%, and 60% across stages I to III, respectively. Within the solid unscreened subgroup, aggregate sensitivity was >75% in 8/18 cancers (44%) and >50% in 13/18 (72%). This multi-cancer early detection test detected cancer signals at high (>75%) sensitivity for multiple cancers without existing population screening recommendations, suggesting its potential to complement recommended screening programs.Clinical trial identifier: NCT02889978.

Evaluation of cell-free DNA approaches for multi-cancer early detection.

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.

Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study.

Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.

Sperm-derived SPANX-B is a clinically relevant tumor antigen that is expressed in human tumors and readily recognized by human CD4+ and CD8+ T cells.

PURPOSE: The sperm-derived SPANX family proteins can be found expressed in human tumors. Here, we aimed to perform a comprehensive study to evaluate immunotherapeutic relevance of one of its members, SPANX-B. We wanted to test its expression pattern in human tumors and to evaluate CD4(+) and CD8(+) T-cell responses in healthy humans after in vitro immunizations. EXPERIMENTAL DESIGN: Expression of SPANX-B in human malignancies, including a multitumor tissue array of 145 primary tumors, was assessed using reverse transcription-PCR, Western blotting, and immunohistochemical analysis. T-cell immunogenicity and immunodominant epitopes of SPANX-B were studied using in vitro immunizations of healthy human donor-derived leukocytes. RESULTS: SPANX-B was abundantly expressed in melanoma and carcinomas of lung, ovary, colon, and breast. In melanoma, tissue array data indicated that it was expressed in advanced and metastatic disease. Unlike most tumor-associated antigens, SPANX-B was an immunogenic antigen that was recognized by circulating T-cell precursors in healthy humans. Importantly, these T cells were readily expanded to generate SPANX-B-specific helper CD4(+) and cytolytic CD8(+) T cells that recognized unique immunodominant epitopes: at least one HLA-DR-restricted Pep-9 epitope (SPANX-B(12-23)) and two HLA-A2-restricted Pep-2 and Pep-4 epitopes (SPANX-B(23-31) and SPANX-B(57-65), respectively). CD8(+) T cells were fully functional to recognize and lyse HLA-A2-expressing tumors, including primary human melanomas. CONCLUSIONS: SPANX-B is an immunogenic sperm-derived antigen that is expressed in several human tumors. SPANX-B is also efficiently recognized by the human T-cell immune arm, indicating its significant value for the development of protective and therapeutic cancer vaccines.

Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer?

Epithelial ovarian cancer is the leading cause of death from gynecological cancer in most of the Western world, and long-term survival remains poor despite good initial response to systemic therapy after debulking surgery. Even after complete pathological response, the risk of recurrence in the first few years is substantial. The peritoneum is the predominant site of failure and the disease remains confined to the peritoneal cavity for much of its course. Efforts to improve clinical outcomes in this group of patients included investigation of intraperitoneal administration of active agents to expose the low-volume postoperative residual disease in the peritoneum to high concentrations of these drugs. In spite of three National Cancer Institute-sponsored randomized trials demonstrating clinical benefit with intraperitoneal therapy in patients with advanced ovarian cancer, the fact remains that it is not uniformly accepted by the gynecologic oncology community in the USA and is rarely used by clinicians in Europe. Intraperitoneal regimens are perceived to be too toxic for administration, although most of the toxicity is reversible. In this article we discuss the available evidence for intraperitoneal chemotherapy, challenges facing the gynecologic oncology community to make this modality more widely acceptable, the selection of patients most likely to tolerate intraperitoneal therapy and ongoing research in this field.

Phase II open-label study of oral piritrexim in patients with advanced carcinoma of the urothelium who have experienced failure with standard chemotherapy.

BACKGROUND: Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report the results of a multiinstitutional, open-label, 2-stage, phase II study that further evaluates oral piritrexim in patients with urothelial carcinoma and who proved nonresponsive to standard chemotherapy. PATIENTS AND METHODS: Eligible patients included those with bi-dimensionally measurable disease and an Eastern Cooperative Oncology Group performance status of 0-2, transitional cell carcinoma or adenocarcinoma of the urothelium, and nonresponse to > or = 1 previous standard chemotherapy regimen. Patients received piritrexim orally at 25 mg 3 times daily (every 8 hours regularly) for 5 consecutive days each week for 3 weeks, followed by a 1-week rest period. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. RESULTS: Of the 23 patients enrolled, 19 patients and 22 patients were assessable for toxicity and response, respectively. Two patients required dose reduction because of toxicity, 2 patients discontinued study because of toxicity, and 6 patients had > or = 1 serious adverse event. Except for grade 1/2 pain and fatigue, gastrointestinal toxicities were the most commonly reported events, followed by fever, delirium, and myelosuppression. No objective responses were observed, with 2 patients demonstrating stable disease after 2-4 cycles. By the statistical design of the trial, further enrollment was halted because of lack of activity. CONCLUSION: Regardless of modest side effects, oral piritrexim in heavily pretreated patients is inactive at this dose and schedule, confirming the results of a recent cooperative group trial.

Recent developments in germ cell tumors of the testes.

PURPOSE OF REVIEW: An overview on several important developments in testicular germ cell tumors in the past year is provided. RECENT FINDINGS: Despite being highly treatable even in advanced stages, recent studies demonstrate that testicular germ cell tumor mortalities can vary significantly in different regions of the world, suggesting limited access to appropriate treatments in certain geographic regions. Several clinically relevant studies on the role of retroperitoneal lymph node dissection in early and advanced stages of disease, and chemotherapy, particularly high-dose chemotherapy in the first-line and salvage settings, were reported. Large databases on testicular cancer survivors were analyzed to further define potentially delayed toxicities of initial treatments for testicular germ cell tumors. SUMMARY: Significant challenges for poor-risk germ cell tumors remain. Treatment paradigms and follow-up strategies for the different stages of testicular germ cell tumors continue to be defined and refined, as research in these areas continues.

Recurrent ovarian cancer.

Ovarian cancer is the most common cause of death from gynecologic malignancies in the United States. Although ovarian cancer is very responsive to multiple chemotherapeutic agents, with objective response rates of up to 80% with the standard platinum and taxane doublets, 75% of patients relapse within 2 years of primary therapy and become candidates for treatment of recurrent disease. Recurrent ovarian cancer is increasingly approached as a chronic disease that requires sequential therapy with available agents. Several issues remain controversial regarding the treatment of patients with recurrent ovarian cancer, including the timing of salvage therapy, choice of agents, and use of monotherapy versus combination regimens. Also, the role of the CA125 tumor marker in detection of recurrence and assessing response to therapy remains unresolved. In this article we address these issues with an emphasis on evidence from the available literature and also discuss the clinical trials that are currently underway to resolve these issues.