Citations

Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p<0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p<0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 <0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 <0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 <0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 <0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB111.

7571 Background: In clinical trials of CAR T-cell therapies and real-world studies published to date, there is a paucity of data on outcomes by race and ethnicity. Here, we examined outcomes by race and ethnicity among LBCL pts who received axi-cel in the real-world setting. Methods: A total of 1389 pts with LBCL were identified from a non-interventional post-authorization safety study with pts receiving commercial axi-cel between 10/2017 and 08/2020. Race (African American or Asian vs White) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Pts with rescinded consent, enrolled in trials, having prior non-HCT cellular therapy, primary CNS lymphoma, unknown comorbidity or data in query were excluded. Median follow-up was 12.7 mo. Outcomes included ORR, CR rate, DOR, PFS and OS, grade ≥ 3 CRS (Lee 2014 criteria) and ICANS (ASTCT consensus grade). ORR and CR were evaluated in pts with ≥ 180 days of follow-up. Kaplan-Meier estimates were calculated for PFS and OS. Multivariable analyses comparing race and ethnicity were conducted via logistic and Cox regression. Results: Among all, 1127 (81%) were White, 70 (5%) African American and 81 (6%) Asian; 152 (11%) were Hispanic including 104 White, 2 Black, and 1 Asian Hispanic. African Americans, compared to White, were younger (median age 55.5 vs 62.8 years), more likely to have pulmonary impairment (41% vs 28%) and tended to have longer time from diagnosis (≥ 12 mo 71% vs 59%). Hispanic pts were younger (median age 58.5 vs 62.6 years) than non-Hispanic pts. ORR was 74% (CR 57%, 12-mo PFS and OS 48% and 63%) for White, 57% (CR 45%, 12-mo PFS and OS 36% and 62%) for African American, 67% (CR 53%, 12-mo PFS and OS 55% and 65%) for Asian and 73% (CR 55%, 12-mo PFS and OS 50% and 65%) for Hispanic pts. Grade ≥ 3 CRS and ICANS occurred in 7% and 18% of African American, 10% and 19% of Asian, and 8% and 27% of White pts, respectively. Hispanic pts had lower rates of grade ≥ 3 CRS and ICANS (4% and 15%) vs non-Hispanic (9% and 27%). African American race was associated with inferior ORR (OR 0.40; 95% CI, 0.24-0.69) and CR rate (OR 0.55; 95% CI 0.32-0.93) vs White. Asian pts had favorable DOR compared to both White (HR 0.46; 95% CI 0.24-0.87) and African American (HR 0.39; 95% CI 0.17-0.88). No statistical differences were found in OS and PFS across races, nor in any efficacy outcome between Hispanic and non-Hispanic pts. Asian (OR 0.52; 95% CI 0.29-0.96 vs White) and Hispanic pts (OR 0.51; 95% CI 0.31-0.85 vs non-Hispanic) had lower risk of grade ≥ 3 ICANS. Conclusions: Overall, axi-cel showed favorable OS, PFS and safety profile regardless of race and ethnicity in the real-world setting. No notable differences in outcomes were observed for Hispanic or Asian pts. Lower response rates in African American pts noted here warrant further investigation including any underrepresentation not explained by a lower incidence rate for DLBCL (SEER), access to care, and disease burden.

Background Prior research has established some risk factors for an increased risk of severe disease and mortality from coronavirus disease 2019 (COVID-19). However, the impact of HIV infection on SARS-CoV-2 susceptibility and severity is a significant gap in the literature. In the same way, not many studies across the globe have analyzed the degree of vaccination willingness among people living with HIV/AIDS (PLWHA) and considerations regarding prioritizing this population during vaccination plans, particularly in developing countries. Methods A descriptive-analytical cross-sectional study was conducted. Self-completed electronic surveys directed to PLWHA were performed via Twitter in February 2021, using accounts of HIV activists. Results 460 (87.1%) participants were willing to be vaccinated with any COVID-19 vaccine. The reasons for that were listed as 1) the belief that vaccination prevents both the COVID-19 infection (81.3%) as well as being a spreader (52.2%); 2) having a high occupational risk of becoming infected with COVID-19 (22%); and 3) the belief that they would be at high risk of death because of COVID-19 (21.3%). Only 56 (10.6%) participants expressed hesitancy toward vaccination, and 12 (2.2%) stated they did not want to get vaccinated. Conclusions Our results may support the prioritization of people living with HIV during the implementation of vaccination plans in developing countries. New strategies should be adopted to overcome the hesitancy and unwillingness toward the COVID-19 vaccination, especially in populations with risk factors for severe disease.

Open reading frame 8 (ORF8) shows one of the highest levels of variability among accessory proteins in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits the presentation of viral antigens by the major histocompatibility complex class I (MHC-I), which interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 in evading immunity and plays a role in SARS-CoV-2 replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein, defines the B.1.1.7 lineage of SARS-CoV-2, engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) with the Q27STOP mutations were identified among 49,055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents, which include Africa, Asia, Europe and South America. Based on various quantitative features, such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, nine possible T-ORF8 unique variants were defined. The question as to whether T-ORF8 variants function similarly to the wild type ORF8 is yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The “Summary of the Guidelines Updates” section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.