Early TP53 Alterations Shape Gastric and Esophageal Cancer Development

Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with a 5-year survival of 32% and 19%, respectively, mainly due to the late-stage diagnosis and aggressive nature of these cancers. Premalignant lesions characterized by atypical glandular proliferation, with neoplastic cells confined to the basement membrane, often precede malignant disease. We now appreciate that premalignant lesions also carry cancer-associated mutations, enabling disease progression in the right environmental context. A better understanding of the premalignant-to-malignant transition can help us diagnose, prevent, and treat GE adenocarcinoma. Here, we discuss the evidence suggesting that alterations in TP53 occur early in GE adenocarcinoma evolution, are selected for under environmental stressors, are responsible for shaping the genomic mechanisms for pathway dysregulation in cancer progression, and lead to potential vulnerabilities that can be exploited by a specific class of targeted therapy.

PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

Lung Cancer Inequalities in Stage of Diagnosis in Ontario, Canada

Lung cancer is the most common cancer and cause of cancer death in Canada, with approximately 50% of cases diagnosed at stage IV. Sociodemographic inequalities in lung cancer diagnosis have been documented, but it is not known if inequalities exist with respect to immigration status. We used multiple linked health-administrative databases to create a cohort of Ontarians 40–105 years of age who were diagnosed with an incident lung cancer between 1 April 2012 and 31 March 2017. We used modified Poisson regression with robust standard errors to examine the risk of diagnosis at late vs. early stage among immigrants compared to long-term residents. The fully adjusted model included age, sex, neighborhood-area income quintile, number of Aggregated Diagnosis Group (ADG) comorbidities, cancer type, number of prior primary care visits, and continuity of care. Approximately 62% of 38,788 people with an incident lung cancer from 2012 to 2017 were diagnosed at a late stage. Immigrants to the province were no more likely to have a late-stage diagnosis than long-term residents (63.5% vs. 62.0%, relative risk (RR): 1.01 (95% confidence interval (CI): 0.99–1.04), adjusted relative risk (ARR): 1.02 (95% CI: 0.99–1.05)). However, in fully adjusted models, people with more comorbidities were less likely to have a late-stage diagnosis (adjusted relative risk (ARR): 0.82 (95% CI: 0.80–0.84) for those with 10+ vs. 0–5 ADGs). Compared to adenocarcinoma, small cell carcinoma was more likely to be diagnosed at a late stage (ARR: 1.29; 95% CI: 1.27–1.31), and squamous cell (ARR: 0.89; 95% CI: 0.87–0.91) and other lung cancers (ARR: 0.93; 95% CI: 0.91–0.94) were more likely to be diagnosed at an early stage. Men were also slightly more likely to have late-stage diagnosis in the fully adjusted model (ARR: 1.08; 95% CI: 1.05–1.08). Lung cancer in Ontario is a high-fatality cancer that is frequently diagnosed at a late stage. Having fewer comorbidities and being diagnosed with small cell carcinoma was associated with a late-stage diagnosis. The former group may have less health system contact, and the latter group has the lung cancer type most closely associated with smoking. As lung cancer screening programs start to be implemented across Canada, targeted outreach to men and to smokers, increasing awareness about screening, and connecting every Canadian with primary care should be system priorities.

Cancer screening utilization in patients diagnosed with cancer types with and without recommended screening modalities.

10557 Background: Several studies have shown screening methods can detect cancer at earlier stages and improve cancer prognosis; however, only four cancer types (breast, colorectal, cervical, and lung) currently have screening methods recommended by the United States Preventive Services Taskforce (USPSTF). In 2021, these four cancers are expected to make up roughly 40% of new cases and cancer deaths, meaning that the majority of cancer deaths will be associated with cancer types lacking recommended screening. We sought to characterize patients who were diagnosed with cancer types with and without recommended screening modalities to demonstrate the gaps in screening faced by the majority of cancers today. Methods: The Geisinger Health System (GHS) Phenomics Initiative Database (PIDB) provides deidentified data from electronic health, billing, and imaging records, and a tumor registry. PIDB was used to identify patients aged 50 to 76 who had cancers diagnosed between 2008 and 2020 and a record of USPSTF-recommended cancer screenings within GHS prior to diagnosis. Analysis focused on patients who received care at GHS during their screening-eligible intervals. Results: Between 2008 and 2020, 13,347 incident invasive cancers were identified in the GHS tumor registry. Of these, 40% (N = 5,331) were cancer types with a recommended screening modality. 57% of these cases (N = 3,039; 23% of all incident cancers) occurred in patients who underwent screening in the interval preceding diagnosis. Screening adherence was significantly associated with stage at diagnosis; patients who were not screened for their diagnosed cancer were more than twice as likely to have a late-stage diagnosis as compared with patients who received screening (multivariate ordinal logistic regression, OR = 2.16, p < 0.001). Patterns of screening adherence in this population are complex; however, 57% of these patients had received screening for a different cancer type. The majority of incident cancers were of those types with no recommended screening modality (N = 8,016; 60% of all incident cancers). Of these, most (N = 6,252; 78%) had been screened for at least one of breast, lung, colon, or cervical cancer and nearly half (N = 3,607; 45%) were current for all guideline-recommended screenings. Not surprisingly, stage at diagnosis was not associated with adherence to any or all screening modalities (multivariate ordinal logistic regression, p = 0.11 and p = 0.45). Conclusions: The majority (79%) of individuals diagnosed with cancer had a history of adherence to at least one screening recommendation. Out of all cancer patients, only 23% were screened specifically for the cancer with which they were subsequently diagnosed, a group that is associated with a lower odds of a late-stage diagnosis. This suggests that the majority of cancer patients who underwent any cancer screening did not benefit from earlier stage diagnosis.

Towards reducing cancer burden within the Medicaid program: Impact of Medicaid expansion on cancer stage at diagnosis.

1572 Background: Studies to date have shown post-Medicaid expansion (M-exp) decreases in the percentage of cancer patients who are uninsured and improvements in cancer stage at diagnosis in states that expanded Medicaid as part of the Affordable Care Act. However, most studies have examined impact of M-exp on stage outcomes at the population level, or among Medicaid and uninsured, rather than solely in the Medicaid population. Using cancer registry data from a non M-exp state (Georgia (GA)) and two M-exp states (Ohio (OH) and New Jersey (NJ)), we compared changes in cancer stage in patients on Medicaid, accounting for individual- and contextual-level characteristics at the Zip Code Tabulation Area (ZCTA) level. Methods: We used GA, OH, and NJ cancer registry data for individuals 20-64 years of age and diagnosed with incident invasive female breast (BC), cervical (CC), and colorectal cancer (CRC). Data spanned from 2010-2017 for GA and OH, and from 2011-2016 for NJ (for BC and CRC only), with 2014 marking the year in which Medicaid was expanded in OH and NJ. We retrieved demographic data (age, race/ethnicity, sex for CRC, insurance status, and cancer stage from the cancer registries), and obtained ZCTA-level data from the American Community Survey (e.g., income, education, and female-headed households). We defined late-stage diagnosis as regional- or distant- stage. We conducted multivariable logistic regression models by state and cancer site to examine changes in late-stage cancer diagnosis pre- and post-M-exp, accounting for individual- and ZCTA-level covariates. Results: The number of patients with incident cancer who were on Medicaid increased by 41.7% (n = 1757 to 2490), 59.6% (327 to 522), and 76.4% (953 to 1681) for BC, CC, and CRC cancers, respectively, in Ohio; by 92.4% (433 to 833) for BC and by over 100% for CRC (232 to 496) in NJ; but by 12.7% (662 to 746) among CRC patients in GA, where the number of BC and CC patients on Medicaid remained relatively stable. Adjusting for individual and contextual-level factors, the adjusted risk ratio (ARR and (95% Confidence Interval)) for late-stage disease was lowest for BC patients in OH (0.93 (0.87, 0.99)) and for CRC patients in GA (0.94 (0.89, 0.99)). The ARR for BC and CRC in NJ were not statistically significant, though they trended towards improvement. Similarly, changes in late-stage for CC were not statistically significant in OH or in GA. Conclusions: The increased number of cancer patients in Medicaid and the reductions in late-stage diagnosis observed may potentially translate into reduced, or at least stabilized, cancer-related morbidity and mortality burden among Medicaid beneficiaries over time. However, reductions in late-stage diagnosis were not consistent across cancer sites or states, possibly due to differences in population demographics, health behaviors, healthcare seeking patterns, and state-level cancer prevention efforts.

Racial/ethnic disparities in oropharyngeal cancer outcomes among males in the United States (2005-2016): A population-based retrospective cohort study.

e18576 Background: The incidence of male oropharyngeal cancers (OPCa) has increased rapidly during the past two decades in the United States. Little is known regarding differences in OPCa incidence and outcomes by race/ethnicity and human papillomavirus (HPV) status. Methods: Population-based retrospective cohort study of 175,843 males diagnosed in U.S. with OPCa from 2005-2016 in the North American Association of Central Cancer Registries. Outcomes included: incidence trends of OPCa by race/ethnicity [Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Other] and histology-based HPV status; late-stage diagnosis; 5-year cumulative and mean survival; and mortality (cause-specific, all cause). Results: The majority of male OPCa were HPV-related (92.2%) and in NHW (83.6%), with marked increase in late-stage HPV-related OPCa among NHW. No difference in late-stage diagnosis was observed between NHW, NHB (aOR, 0.99, 95% CI, 0.94-1.04), and Hispanics (aOR, 0.98, 95% CI, 0.92-1.04), while other race had lower odds of late-stage diagnosis (aOR 0.87, 95% CI, 0.79-1.01). HPV-related cancers (aOR, 3.47, 95% CI, 3.33-3.62), Medicaid (aOR, 1.37, 95% CI, 1.28-1.46) and no insurance (aOR, 1.44, 95% CI, 1.32-1.56) were independent predictors of late-stage diagnosis. NHB (69.72 months, 95% CI, 68.14-71.31) and Hispanics (91.89 months, 95% CI, 89.87-93.91) had lower unadjusted mean survival in HPV-related OPCa relative to NHW (99.63 months, 95% CI, 99.18-100.07; p < 0.01). Higher cancer-specific mortality was observed among NHB (aHR, 1.79, 95% CI, 1.71-1.86), Hispanics (aHR, 1.07, 95% CI, 1.01-1.14), HPV-related OPCa (aHR, 1.17, 95% CI, 1.11-1.24), age > 54 years, insurances other than private, residence in counties with higher poverty, and geographic regions other than the Northeast. Adjusting for treatment attenuated associations but did not eliminate the observed cancer-specific mortality, except in Hispanics and residence in the South. Conclusions: There has been a sharp increase in HPV-related late-stage OPCa among NHW males over the past decade. Despite no racial/ethnic differences in late-stage diagnosis, NHB had highest mortality that was not explained by treatment. HPV vaccination and possibly, oral cancer screening should be promoted, especially in NHW males. Further research is needed to elucidate comorbidities and possible biologic mechanisms responsible for the higher OPCa mortality among NHB males.