Abstract An accumulating body of evidence suggests carriers of a pathogenic germline variant (PGV) in BRCA1 or BRCA2 have increased gastric cancer (GC) risk. BRCA1 and BRCA2 are tumor suppressor genes involved in promoting homologous recombination to repair double-stranded DNA breaks. The aim of this investigation was to identify differences within the gastric epithelium and in patient-derived gastric organoids (PDGOs) between BRCA1 and BRCA2 carriers and non-carriers to determine if evidence of early gastric carcinogenesis exists amongst these carriers. First, using gastric epithelial biopsies, BRCA2 carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium and strikingly, biopsies from both BRCA1 and BRCA2 carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, where a growth advantage was observed for both BRCA1 and BRCA2 PDGOs compared to non-carrier PDGOs. Furthermore, both BRCA1 and BRCA2 PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double stranded DNA damage compared to non-carrier PDGOs. Importantly, none of the PDGOs showed signs of BRCA1 or BRCA2 loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in BRCA1 and BRCA2 carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to GC development. 

Gastric epithelium from BRCA1 and BRCA2 carriers harbors increased double-stranded DNA damage and augmented growth

Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the TP53 gene, leading to a significantly increased risk of developing various cancers at a young age, including breast cancer. 

Her2-positive breast cancer in a young patient with Li-Fraumeni syndrome: A comprehensive case study

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Background: Chemotherapy induced alopecia is one of the most distressing side effects of cancer therapy since it is a constant reminder of the underlying malignancy. Anthracycline chemotherapy induces total alopecia. Although scalp cooling devices have been used to prevent this alopecia, there is still a need to improve efficacy with anthracycline therapy. This study was performed to evaluate if the Paxman Scalp Cooling System is safe, tolerable, and more efficacious at lower temperatures.
 Objectives: The primary end point is to assess the safety and tolerability of the Paxman Scalp Cooling System at lower temperatures (-7.5 Celsius and -10 Celsius), defined as the ability of patients to undergo scalp cooling without any DLTs during the treatment period. The secondary end point is successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [< 50% hair loss not requiring a wig] were considered to have hair preservation) after anthracycline chemotherapy.
 Methods: 34 women with stage I-III breast cancer who were receiving anthracycline-based neoadjuvant or adjuvant therapy were enrolled on study. The first 7 patients received scalp cooling at -7.5 Celsius and the subsequent 27 patients received scalp cooling at -10 Celsius. Patients completed safety and tolerability assessments at each visit. In addition, participants had standardized scalp photography to assess the superior, vertex and frontal scalp views, trichoscopic assessments, alopecia grading and completed PROs (CADS, Tolerability, Change in scalp coverage).
 Results: Thirty-four women (56% White, 18% Black, 8% Asian, 18% other) with a mean age of 44 (range 20-68) were enrolled on this IRB-approved pilot study. Seventy-four percent received ddAC-T, 18% received ddAC-THP and 8% received ddAC/Pembro-T/Carbo/Pembro. Twenty-six patients were evaluable for the DLT end point. Three patients are still on study and five patients left the study before completion (2 due to lack of efficacy, 1 shaved her head, 1 was removed from study due to hospitalization for sepsis and 1 patient changed her mind and never started scalp cooling). There were no DLTs in any patient throughout the study. Both the -7.5 and -10 Celsius temperatures were found to be tolerable with no difference in tolerability. The most common reported AEs were headaches 48%, discomfort 13%, scalp pain 9.7%, dizziness 9.6%, scalp coldness 6%, feeling cold 3% and lightheadedness 3%. Twenty-nine percent of patients reported that scalp cooling triggered a headache and the average level of pain was mild. Only 16% of patients reported pain killer use due to scalp cooling, which effectively resolved headaches or discomfort. Sixty-one percent of patients reported hair preservation at the primary end point. Hair regrowth was reported in patients after they experienced grade 2 alopecia and while still on study. More detailed data on hair preservation will be forthcoming once all of the photos and trichoscopic measures are assessed.
 Conclusions: Paxman Scalp Cooling System is safe, tolerable and even more efficacious at lower temperatures. The -10 Celsius is more efficacious and as tolerable as -7.5 in patients being treated with anthracycline therapy. When using the Paxman Scalp Cooling System in patients being treated with anthracycline therapy, you should consider performing scalp cooling at lower temperatures
 Table 1: Demographics
 Citation Format: Shari B. Goldfarb, Victoria Blinder, Devika Gajria, Cassandra Chang, Analisa Dacunto, Jinae Park, Monica Fornier, Mario Lacouture. Safety and Tolerability of Paxman Scalp Cooling at Lower Temperatures to Improve Efficacy with Anthracycline Chemotherapy [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 P5-08-10.

Abstract P5-08-10: Safety and Tolerability of Paxman Scalp Cooling at Lower Temperatures to Improve Efficacy with Anthracycline Chemotherapy


 Most BC patients succumb to metastatic relapse years to decades following primary tumor resection due to reactivation of dormant disseminated cancer cells (DCCs). Improved BC patient survival has led to metastatic relapse manifesting in an older patient population. This population carries somatic mosaicism in many organs including bone marrow. Age-specific somatic mutations (e.g., DNMT3A, ASXL1, TET2) in hematopoietic stem and progenitor cells (HSPCs) results in CH, which is associated with increased inflammatory myeloid cells and risk of leukemia and intriguingly with BC-specific mortality. In this presentation I will discuss new data from a team effort to test the hypothesis that CH myeloid cells could shape target organs niches that harbor dormant DCCs to be pro-metastatic. This hypothesis has been explored in clinical trials data where the presence of CH in ER+ and HER2+ metastatic BC patient cohorts (MSK-IMPACT) was associated with the response to first line CDK4/6i/endocrine therapy or taxol/herceptin/pertuzumab, respectively. We also tested whether CH can accelerate dormant DCC awakening in a murine model of CH carrying mutations in DNMT3A (KO or point mutation) and HER2+ mammary cancer. We propose our work may provide unprecedented insights into how a traceable age-related-mosaicism in the bone marrow (CH) may shape distant organs to be drive metastatic relapse.
 Citation Format: Julio A. Aguirre-Ghiso, Michael Papanicolaou, Pablo Sánchez Vela, Julie Yang, Anton Safonov, Jacqueline Tao, Sebastia Franch Exposito, Vera Tiedje, Erica Dalla, Luis E. Valencia Salazar, Nicole Barth, Merve Sahin, Kevin Chen, Jinae Park, Matthew Wereski, Aishwarya Krishnan, Anthony Martinez Benitez, Ryan Ptashkin, Mark E. Robson, Elisa de Stanchina, Lior Z. Braunstein, Ahmet Zehir, Elizabeth Comen, Larry Norton, Michael Berger, Richard Koche, Pedram Razavi, Ross Levine. Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY34-02.

Abstract SY34-02: Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening

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Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract P5-08-10: Safety and Tolerability of Paxman Scalp Cooling at Lower Temperatures to Improve Efficacy with Anthracycline Chemotherapy

Abstract SY34-02: Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening