American Association For Cancer Research Research Articles

Abstract 930: Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations

Abstract Background: Limited information is available about treatments and clinical outcomes among men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor DNA damage repair (DDR) mutations. Methods: This retrospective chart review study included men diagnosed with mCRPC with ≥1 DDR mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the initiation of a new therapy in this period, in patients who developed castration-resistant disease and progressed while receiving androgen deprivation therapy. Data on all available lines of therapy post-index were collected. Outcomes reported include time to treatment discontinuation for any reason (TTTD) and overall survival (OS), which were assessed using Kaplan-Meier analyses. Results for tumor response-related endpoints are forthcoming. Results: A total of 138 patients with mCRPC met the inclusion criteria. The mean age at index was 68 years, and 76% of patients were White. The median follow-up time was 27.1, 15.9, 11.3, and 9.4 months for 1L, 2L, 3L, and 4L+ therapy, respectively. Common sites of metastases included bone (74%), lymph nodes (69%), and lungs (10%). Common tumor DDR mutations included CDK12 (48%), BRCA2 (23%), ATM (21%), and BRCA1 (8%). Assessment of germline mutations was conducted in 114 (83%) patients; the most common was BRCA2 (8%). First-line (1L) treatment information was available for 119 (86%) patients, 2L for 101 (73%), and 3L for 75 (54%) patients. Novel hormonal therapy (NHT; 55%) and taxane chemotherapy (20%) were most common in 1L. Enzalutamide (35%) and abiraterone acetate (14%) were the most frequently used NHTs. Compared to 1L, the proportion of patients receiving NHTs was lower in 2L (33%) and 3L (17%), while the proportion of patients receiving taxanes was higher (36% in 2L and 31% in 3L). In 3L, poly ADP-ribose polymerase (PARP) inhibitors were used in 21% of patients. Median TTTD was 5.6 months (95% CI: 4.2, 7.2) in 1L, 3.9 months (95% CI: 3.0, 4.6) in 2L, and 4.0 months (95% CI: 3.3, 4.7) in 3L. Median OS was 36.3 months (95% CI: 30.7, 47.8) from the start of 1L, 21.1 months (95% CI: 15.6, 29.3) from the start of 2L, and 14.1 months (95% CI: 9.5, 20.5) from the start of 3L. Conclusions: These findings provide real-world insights about treatment patterns and clinical outcomes among patients with mCRPC harboring DDR mutations. Such insight may provide a helpful benchmark for research aimed at improving clinical outcomes, particularly in later lines of therapy. Citation Format: David B. Solit, Niharika B. Mettu, Shannon J. McCall, Mallika Dhawan, Priyanka J. Bobbili, Maral DerSarkissian, Jasmina Ivanova, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Tracy Guo, Mei Sheng Duh, William K. Oh. Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 930.

Abstract NG13: Feasibility of topical self-administered therapies to improve cervical precancer treatment outcomes among women living with HIV in low-and middle-income countries

Abstract Global trends of invasive cervical cancer (ICC) represent a dire global health inequity, with 85 percent of incident cases and 90 percent of deaths occurring in low- and middle-income countries (LMICs).1 ICC is the leading cause of cancer death among women living with HIV (WLWH) in sub-Saharan Africa, which accounts for 71% of the global burden of HIV infection, despite being home to only 12% of the global population.2 Compared to HIV-negative women, WLWH have increased incidence and persistence of human papillomavirus (HPV),3 have a shorter time from HPV infection to development of precancerous lesions,4 and have a six to eightfold increased risk of developing invasive cancer.5 In 2020, the World Health Organization (WHO) launched the 90/70/90 global strategy for cervical cancer elimination, which aims for 90% human papillomavirus (HPV) vaccination rate, 70% screening coverage, and 90% of precancerous lesions adequately treated by 2030. Current efforts towards this elimination agenda include scaling up HPV-based screening programs as well as improving access to precancer treatment using portable ablation and excisional devices in LMICs. However, among WLWH, current precancer treatment methods are limited by high rates of treatment failure. In a randomized trial of WLWH with cervical intraepithelial neoplasia grade 2/3 (CIN2/3), recurrence at 24 months was 30% in the ablation arm and 19% in the excision arm.6 These high rates of treatment failure, demonstrated in multiple studies, are driven by persistent HPV infection following treatment,7 and are highly consequential in LMICs settings follow-up mechanisms are weak. This highlights an urgent need for studies on feasible, innovative, yet accessible strategies to improve HPV clearance following precancer treatment for WLWH in LMICs. Use of self-administered topical therapies with anti-viral properties as adjunct treatment could be a feasible and highly scalable strategy to address this limitation. Several studies, have demonstrated the safety, and efficacy of 5-Flourouracil (5FU), a readily available topical drug as primary or adjuvant therapy for CIN2/3 among both HIV-positive and HIV-negative women in the U.S. In a Phase III multicenter trial of U.S WLWH with CIN2/3 randomized to self-administered intravaginal 5-Flourouracil (5FU) versus observation following standard treatment, participants in the 5FU arm had an 8% CIN2/3 recurrence rate at 18 month follow-up, compared to 31% in the observation arm (p=0.04).8 In another randomized trial of self-administered 5FU as primary treatment versus 6-month observation for CIN grade 2 (CIN2) among U.S women without HIV infection, 93% in the 5FU arm had disease regression, compared to 56% in the observation arm (p=0.01).9 In this study, 50% of participants in the 5FU arm cleared HPV at follow-up, compared to 22% in the observation arm (p<0.05). In both studies, 5-FU, used once every other week for 8 applications, was safe, with no grade 3 or 4 adverse events, and compliance and adherence to treatment was high. However, there are no studies evaluating whether self-administered therapies would be culturally acceptable to WLWH and their male partners in LMICs, or whether topical 5FU may be in this population. To fill this gap, with the support of the 2022 Victoria’s Secret Global Fund for Women’s Cancers Career Development award, in partnership with Pelotonia & the American Association for Cancer Research, using in-depth-interviews and focus group discussions, I am carrying out a mixed-methods qualitative study among WLWH with HPV and their male partners in Kenya and Malawi to investigate their perceptions towards using self-administered therapies for HPV and cervical precancer treatment, as well as perceived barriers and facilitators to uptake. Additionally, I will conduct a Phase I trial to evaluate the safety and adherence of self-administered intravaginal 5-FU following primary treatment among WLWH with CIN2/3 in Kenya. These studies will generate key preliminary data to support future randomized trials to investigate the efficacy of 5FU as adjuvant therapy to improve current precancer treatment strategies for WLWH in LMICs.

Abstract P4-01-30: Real-world treatment patterns and survival among adults with metastatic breast cancer with BRCA1/2 mutations

Abstract Background: Limited information is available about real-world treatment patterns and survival among patients with metastatic breast cancer (mBC) with BRCA1/2 mutations. BRCA1/2 mutations, which are involved in the repair of DNA double-strand breaks, are rare. Since 2018, PARP inhibitors (olaparib and talazoparib) have been approved for the treatment of patients with germline BRCA-mutated HER2-negative locally advanced and/or mBC. Methods: This retrospective chart review study included adults diagnosed with mBC with ≥1 oncogenic somatic BRCA1/2 mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at 3 oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the first initiation of a new therapy for mBC in this period (which could be first-line [1L] or subsequent line of therapy). Data on all available lines of therapy post-index were collected. Treatments received in different lines of therapy for mBC and overall survival (OS) were described separately for patients with HR-positive/HER2-negative (HR+/HER2-) mBC, triple negative mBC (TNBC), and HER2-positive (HER2+) mBC. OS from the start of each line of therapy was assessed using Kaplan-Meier analysis. Results: A total of 48 women with mBC met the inclusion criteria. The mean age at index was 58 years; 73% of women were White. Common sites of metastases included lymph nodes (56%), bone (52%), and lungs (31%). Somatic BRCA1 mutation was detected in 48% and BRCA2 mutation was detected in 54% of women. Assessment of germline BRCA mutations was conducted in 25 (52%) women; 2 (8%) of assessed women tested positive for germline BRCA mutations. 29 (60%) of women had HR+/HER2- mBC, 9 (19%) had TNBC, 9 (19%) had HER2+ mBC, and 1 woman had unknown HER2 status. Treatments received in different lines of therapy for mBC and OS from start of each line of therapy by HR and HER2 status are reported in Table 1. Common treatments for women with HR+/HER2- mBC included endocrine-based therapy, and chemotherapy. Women with TNBC were most often treated with chemotherapy. Women with HER2+ mBC most often received endocrine-based therapy in 1L; chemotherapy or HER2-targeted combination therapy in second-line (2L); and chemotherapy or HER2-targeted monotherapy in third-line (3L). Median OS from the start of 1L therapy was 37.5 months among women with HR+/HER2- disease; 20.0 months for women with TNBC; and 51.7 months for women with HER2+ disease. Conclusions: These findings provide real-world insights about treatment patterns and survival among women with mBC and BRCA1/2 mutations. Further studies with larger sample sizes are needed to confirm these findings. Table 1. Treatment patterns and survival by line of therapy, HR, and HER2 status among patients with BRCA1/2 mutated mBC Citation Format: Priyanka Bobbili, Jasmina Ivanova, David B. Solit, Niharika Mettu, Shannon McCall, Mallika Dhawan, Maral DerSarkissian, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha J. Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Mianzhao Guo, Mei Sheng Duh, William Oh. Real-world treatment patterns and survival among adults with metastatic breast cancer with BRCA1/2 mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-30.

Editorial Introductions.

Current Opinion in Oncology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of psychiatry is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Gil AwadaGil AwadaGil Awada (1990) studied medicine at the Vrije Universiteit Brussel (Brussels, Belgium), graduating in 2015, and subsequently started his training in Internal Medicine. In June 2021, he successfully defended his PhD thesis entitled ‘Expanding the application of targeted therapies and immune checkpoint inhibitors in advanced melanoma and recurrent glioblastoma’, under the supervision of Prof. Dr. Bart Neyns. He is currently finishing his residency in Medical Oncology at the Jules Bordet Institute, Belgium. Gil Awada performs clinical and translational research in the field of melanoma, investigating new applications of targeted agents, combination therapies and the use of novel clinical biomarkers (such as circulating tumor DNA and imaging). His work has been presented at national and international congresses and has been published in peer-reviewed journals. Oliver BechterOliver BechterOliver Bechter earned his MD at the University of Innsbruck, Medical School in Austria in 1998. During his residency he did a postdoctoral fellowship at the Department of Cell Biology, UTSouthwestern in Dallas, TX, USA. He earned his PhD in 2005 and is a board-certified Medical Oncologist and Hematologist since 2007. Since 2012 he is working at the University Hospital in Leuven Belgium and is a professor for Oncology at the Department of Oncology from the KU Leuven. His research focus is telomere biology in human malignancies and melanoma biology. His clinical focus is on malignant melanoma and skin cancers and he is principal investigator of several clinical trials with a focus on drug development of new immune-oncology drugs in melanoma. Jana JeschkeJana JeschkeJana Jeschke studied molecular medicine at the University of Erlangen-Nuremberg, Germany, and performed her PhD research at the Johns Hopkins University in Baltimore, USA, in the groups of Prof. Nita Ahuja and Prof. Jim Herman and in collaboration with Prof. Baylin. During this time, she made several important discoveries in the field, including the identification and functional characterization of aberrantly DNA methylated genes in breast cancer and their assessment as novel biomarkers. In 2013, Dr Jeschke moved to Belgium to start a postdoctoral training in the Laboratory of Cancer Epigenetics at Université Libre de Bruxelles (ULB) in Brussels. Under the supervision of her lead mentor Prof. Fuks and his long-time collaborator Prof. Sotiriou, a breast cancer expert from the Jules Bordet Institute in Brussels, she explored changes of various epigenetic modifications on DNA and RNA in breast and other cancers and the clinical relevance of these aberrations for cancer diagnosis and therapy. Her most notable works include the development of an epigenetic immune signature that predicts survival and response to chemotherapy in breast cancer (JCI 2017) and the discovery of m6A mRNA methylation changes in breast cancer and their impact on pathways driving cancer progression and therapy resistance (Nature Cancer 2021). For her research, Dr Jeschke was awarded a postdoctoral fellowship from the Belgian National Fund for Scientific Research (FNRS) in 2014. In 2022, she obtained the mandate of Chercheuse Qualifiée (Associate Professor) from the FNRS to start her own research group at ULB focusing on precision cancer epigenetics. Dr Jeschke is a member of the Belgian Association for Cancer Research (BACR), European Association for Cancer Research (EACR), American Association for Cancer Research (AACR) and Cancer Epigenetics Society (CES) and a consultant for the “Belgian Superior Health Council”. She is an associate editor for the journal of Current Opinion in Oncology and regularly reviews for other journals publishing studies related to cancer and epigenetics.

Translating Science into Survival: Report on the Sixth International Cancer Immunotherapy Conference.

From September 28 to October 1, 2022, in New York City, the Sixth International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute (CRI), the American Association for Cancer Research, and the European Network for Cancer Immunotherapy. The four-day event covered the latest advances in cancer immunology and immunotherapy.

The legacy is not just with you: an interview with Stephen Baylin.

The legacy is not just with you: an interview with Stephen Baylin.

54P Fallopian tube cancer and ovarian cancer: A real-world comparison of epidemiological patterns, clinical outcomes, and mutational landscape

Fallopian tube cancer is a rare tumor which accounts for only 1% of all gynaecological cancers. It is closely related and generally treated with a similar approach to ovarian cancer. We used the publicly available databases to provide a description of epidemiological patterns, clinical outcomes, and mutational landscape of fallopian tube cancer and compare it with that of ovarian cancer. We extracted clinical and epidemiological data of fallopian tube and ovarian cancers from the SEER database [13 reg; Nov 2020 Submission]. The average annual percentage change (AAPC) of incidence rates was calculated using The NIH’s Joinpoint Regression Program. Sequencing data were obtained through The American Association of Cancer Research (AACR) project GENIE database. We included 4,240 cases of fallopian tube cancer and 74,837 cases of ovarian cancer diagnosed between 1992 and 2018. The overall incidence of fallopian tube cancer was 0.39 [95% CI, 0.38-0.40], whereas the overall incidence of ovarian cancer was 6.97 [95% CI, 6.92-7.02]. Between 1992 and 2018, there was a significant increase in the incidence of fallopian tube cancer (AAPC = 6.1% 95% CI, [4.6, 7.9], p<0.001) and a decrease in the incidence of Ovarian cancer (AAPC = -1.7% 95% CI, [-2, -1.4], p<0.001). The median overall survival of fallopian tube cancer was significantly higher than ovarian cancer (80 months vs 43 months, P<0.001). A presentation with stage IV disease was significantly less frequent in fallopian tube cancer compared to ovarian cancer (50% vs 70%, P<0.001). In 166 patients with fallopian tube cancer and 5,303 patients with ovarian cancer in GENIE, the most frequently mutated genes were TP53, SPTA1, LRP1B, FAT3, and NF1; and TP53, CSMD3, DNAH9, ARID1A, and PDE4DIP; for fallopian tube cancer and ovarian cancer respectively. Fallopian tube cancer is a distinct disease entity different in genetic, epidemiological, and clinical characteristics from ovarian cancer. Cases with fallopian tube cancer are less likely to present with distant metastasis and have longer overall survival compared to cases with ovarian cancer. The most frequently mutated genes of both cancers are different.

22MO Homologous recombination gene mutations in uterine serous cancer: A phenotype of the hereditary breast and ovarian cancer syndrome?

To determine the prevalence of somatic homologous recombination (HR) gene mutations in uterine serous cancer (USC) and compare these with rates among high-grade serous ovarian cancer (HGSOC). The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing genomic profiles of tumor samples. Mutation frequencies for 8 homologous recombination deficiency (HRD) genes are reported and compared between uterine serous cancer (USC) and high-grade serous ovarian cancer (HGSOC) samples using chi-squared or Fisher's exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Table: 22MOComparison of mutation frequencies of HR genes between tumor samples from uterine serous cancer and high-grade serous ovarian cancerMutation frequency among USCMutation frequency among HGSOCP-valueBRCA112/776, 1.5%313/3125, 10.0%p<0.001BRCA240/776, 5.2%218/3125, 7.0%p<0.001BRIP14/752, 0.5%57/2974, 1.9%p<0.01CHEK26/768, 0.8%19/3040, 0.6%0.82BARD112/664, 1.8%55/2615, 2.1%0.74RAD51C3/671, 0.4%27/2663, 1.0%0.25RAD51D4/671, 0.6%24/2658, 0.9%0.59PALB212/766, 1.6%37/3045, 1.2%0.58 Open table in a new tab Among 844 USC samples, the most prevalent somatic HR gene mutations were BRCA2 (5.2%), BARD1 (1.8%), PALB2 (1.6%) and BRCA1 (1.5%). When compared to 3304 HGSOC samples, higher HR gene mutation frequencies among HGSOC were only found for BRCA1 (10.0% vs 1.5%, p<0.001), BRCA2 (7.0% vs 5.2%, p<0.001) and BRIP1 (1.9% vs 0.5%, p<0.01); however, there was no difference between HGSOC and USC samples in mutation frequencies of BARD1, CHEK2, RAD51C, RAD51D or PALB2. Genomic profiling of USC tumor samples demonstrates a substantial rate of somatic gene mutations conferring HR deficiency, with rates for most HR gene mutations similar to those found among HGSOC samples. This demonstrates the need for genetically targeted clinical trials of poly-ADP ribose polymerase (PARP) inhibitors in patients with USC, and further research into the germline genetic profile of these patients to establish if this rare uterine cancer could be a phenotype of the hereditary breast and ovarian cancer syndrome.

Analysis of histology-agnostic targets among soft tissue and bone sarcomas in the AACR GENIE database.

The development of novel therapies for patients with sarcoma is challenging due to the rarity and diversity of these mesenchymal neoplasms. Hence, histology-agnostic approvals can be of particular interest for the treatment of patients with soft tissue and bone sarcoma. We queried the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database Cohort v12.0-Public to investigate the prevalence of currently Food and Drug Administration (FDA)-approved and other potentially actionable histology-agnostic alterations in patients with soft tissue and bone sarcoma. Targets were identified by a literature review by the authors. Results are presented for each cohort identified in the GENIE database, namely: (1) soft tissue sarcoma (STS), (2) gastrointestinal stromal tumor (GIST), (3) bone sarcoma, (4) uterine sarcoma, and (5) breast sarcoma. We identified 7,512 samples of 6,955 patients with sarcoma in the AAACR GENIE database v12.0-Public. Molecular alterations that could lead to the clinical use of a currently approved histology-agnostic therapy were identified in 2.1% of sarcomas (2.6% STS, 1.3% GIST, 1.4% bone, 2.7% uterine, and 0% breast). In addition, 2.9% of patients could be eligible for future histology-agnostic approvals. These specific mutations, fusions, and amplifications occurred in multiple histotypes in all cohorts. Exploring a public large-scale genomic database, we identified that 5% of patients with sarcoma could be eligible for current histology-agnostic FDA-approved drugs or future potential histology-agnostic indications. These actionable alterations were present in a wide variety of histologies in soft tissue and bone sarcomas, highlighting that next-generation sequencing can be considered for patients with advanced sarcoma to guide treatment strategies.

Cancer Immunology Research: A Decade of Illumination and Innovation

<i>Cancer Immunology Research</i>: A Decade of Illumination and Innovation

Abstract B084: The Florez Lab at Dana-Farber Cancer Institute: Improving the care of vulnerable populations and supporting trainees from underrepresented groups in medicine

Abstract Background: Racial and ethnic minorities have well-established disparities in cancer prevention, detection, treatment, and survival. A diverse oncology workforce improves the gap in cancer care for vulnerable populations. However, physicians, researchers, and others who are Underrepresented in Medicine (UIM) face unique challenges in obtaining mentorship and sponsorship, and there is a lack of safe spaces for them to thrive, forcing many to leave medicine entirely. To further efforts in improving the care of vulnerable populations and to create a welcoming environment for UIM medical trainees, the Florez Lab (formerly known as the Duma Lab) was founded by Dr. Narjust Florez in 2019 at the University of Wisconsin. Subsequently, Dr. Florez moved to Dana-Farber Cancer Institute and expanded the lab’s reach. Here, we describe the history and legacy of our innovative group. Methods: The Florez Lab is composed of 39 members, mostly UIM from different backgrounds and locations; members range from college students to faculty. It began as an all-female team but now includes #HeforShe member allies. Several members joined as trainees, but are now junior faculty at NCI designated cancer centers and pay it forward by mentoring the next generation of the Florez Lab. We focus on social justice issues in medicine, including discrimination and gender bias in academic and clinical medicine, global oncology, and cancer health disparities, with a focus on thoracic oncology. Results: To date, the Florez Lab has secured research funding from several institutions and organizations, and has published 15 original articles, 11 editorials, 4 review articles, and 2 book chapters in addition to over 20 poster presentations at national and international conferences. Members have presented research findings at a wide array of national and international conferences, including the American Society of Clinical Oncology (ASCO) Annual Meeting and the World Conference on Lung Cancer, and the American Association for Cancer Research (AACR) Annual Meeting. The lab collaborates with multiple organizations, including the COVID-19 and Cancer Consortium (CCC19), ASCO Health Equity Committee, and the Lancet Commission: Women &amp; Cancer. The lab is far-reaching; the #DumaLab and #FlorezLab hashtag is used on Twitter to amplify published work and advocacy efforts in improving the diversity of the oncology workforce and clinical trial enrollment. In 2021 the Florez Lab began a collaboration with Medscape and is the first lab to have a dedicated column, where we discuss issues related to social justice in medicine and cancer health disparities; the column has reached over 60,000 readers in less than one year. Conclusion: The success of the Florez Lab illustrates the importance of providing opportunities for, supporting, and amplifying the success of UIM trainees. Results indicate that the collaboration of UIM trainees is productive, meaningful, and necessary. Efforts should be made to continue supporting UIM trainees from all backgrounds and levels. Citation Format: Narjust Florez, Inas Abuali, Ana Velazquez, Coral Olazagasti, Idalid Franco, Shruti Patel, Cristiane Bergerot, Paulo Bergerot, Enrique Soto Pérez, Carolina Bernabe-Ramirez, Lauren Kiel. The Florez Lab at Dana-Farber Cancer Institute: Improving the care of vulnerable populations and supporting trainees from underrepresented groups in medicine [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B084.

Concurrent dose-finding of a novel cancer drug with and without a second agent.

More complex research questions are being posed in early-phase oncology clinical trials, necessitating design strategies tailored to contemporary study objectives. This paper describes the proposed design of a Phase I trial concurrently evaluating the safety of a hematopoietic progenitor kinase-1 inhibitor (Agent A) as a single agent and in combination with an anti-PD-1 agent in patients with advanced malignancies. The study's primary objective was to concurrently determine the maximum tolerated dose (MTD) of Agent A with and without anti-PD-1 therapy among seven possible study dose levels. Our solution to this challenge was to apply a continual reassessment method shift model to meet the research objectives of the study. The application of this method is described herein, and a simulation study of the design's operating characteristics is conducted. This work was developed through collaboration and mentoring between the authors at the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual AACR/ASCO Methods in Clinical Cancer Research Workshop. The aim of this manuscript is to highlight examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying modern design conditions. Although the design is presented using an investigation of Agent A with and without anti-PD-1 therapy as an illustrative example, the approach described is not specific to these agents and could be applied to other concurrent monotherapy and combination therapy studies with well-defined binary safety endpoints.

The importance of being generous.

Lisa M. Coussens is Professor and Chair of the Cell, Developmental and Cancer Biology department, and Deputy Director of Basic and Translational Research in the Knight Cancer Institute, at Oregon Health and Science University in Portland Oregon, USA. She is also President of the American Association for Cancer Research (AACR) for 2022–2023. Nature Cancer caught up with her to hear her thoughts on the past year and what’s in store for 2023.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

Electronic Nicotine Delivery Systems: An Updated Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology.

Combustible tobacco use has reached historic lows, demonstrating the importance of proven strategies to reduce smoking since publication of the 1964 Surgeon General's report. In contrast, the use of electronic nicotine delivery systems (ENDS), specifically e-cigarettes, has grown to alarming rates and threatens to hinder progress against tobacco use. A major concern is ENDS use by youth and adults who never previously used tobacco. While ENDS emit fewer carcinogens than combustible tobacco, preliminary evidence links ENDS use to DNA damage and inflammation, key steps in cancer development. Furthermore, high levels of nicotine can also increase addiction, raise blood pressure, interfere with brain development, and suppress the immune system. The magnitude of long-term health risks will remain unknown until longitudinal studies are completed. ENDS have been billed as a promising tool for combustible tobacco cessation, but further evidence is needed to assess their potential efficacy for adults who smoke. Of concern, epidemiological studies estimate that approximately 15% to 42% of adults who use ENDS have never used another tobacco product, and another 36% to 54% "dual use" both ENDS and combustible tobacco. This policy statement details advances in science related to ENDS and calls for urgent action to end predatory practices of the tobacco industry and protect public health. Importantly, we call for an immediate ban on all non-tobacco-flavored ENDS products that contain natural or synthetic nicotine to reduce ENDS use by youth and adults who never previously used tobacco. Concurrently, evidence-based treatments to promote smoking cessation and prevent smoking relapse to reduce cancer incidence and improve public health remain top priorities for our organizations. We also recognize there is an urgent need for research to understand the relationship between ENDS and tobacco-related disparities.

Electronic Nicotine Delivery Systems: An Updated Policy Statement From the American Association for Cancer Research and the American Society of Clinical Oncology.

Combustible tobacco use has reached historic lows, demonstrating the importance of proven strategies to reduce smoking since publication of the 1964 Surgeon General's report. In contrast, the use of electronic nicotine delivery systems (ENDS), specifically e-cigarettes, has grown to alarming rates and threatens to hinder progress against tobacco use. A major concern is ENDS use by youth and adults who never previously used tobacco. While ENDS emit fewer carcinogens than combustible tobacco, preliminary evidence links ENDS use to DNA damage and inflammation, key steps in cancer development. Furthermore, high levels of nicotine can also increase addiction, raise blood pressure, interfere with brain development, and suppress the immune system. The magnitude of long-term health risks will remain unknown until longitudinal studies are completed. ENDS have been billed as a promising tool for combustible tobacco cessation, but further evidence is needed to assess their potential efficacy for adults who smoke. Of concern, epidemiological studies estimate that approximately 15%-42% of adults who use ENDS have never used another tobacco product, and another 36%-54% dual use both ENDS and combustible tobacco. This policy statement details advances in science related to ENDS and calls for urgent action to end predatory practices of the tobacco industry and protect public health. Importantly, we call for an immediate ban on all non-tobacco-flavored ENDS products that contain natural or synthetic nicotine to reduce ENDS use by youth and adults who never previously used tobacco. Concurrently, evidence-based treatments to promote smoking cessation and prevent smoking relapse to reduce cancer incidence and improve public health remain top priorities for our organizations. We also recognize there is an urgent need for research to understand the relationship between ENDS and tobacco-related disparities.