Dana-Farber Research Publication 03.15.2024

Welcome to Dana-Farber's Research News

March 15, 2024

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.

Cancer Discovery

Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma

Choueiri TK, Braun DA

The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ?2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes.

SIGNIFICANCE: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens.

Journal of Clinical Oncology

Adolescent and Young Adult Germ Cell Tumors: Epidemiology, Genomics, Treatment, and Survivorship

Frazier AL

Innovations in the care of adolescent and young adult (AYA) germ cell tumors (GCTs) are needed for one of the most common AYA cancers for which treatment has not significantly changed for several decades. Testicular GCTs (TGCTs) are the most common cancers in 15- to 39-year-old men, and ovarian GCTs (OvGCTs) are the leading gynecologic malignancies in women younger than 25 years. Excellent outcomes, even in widely metastatic disease using cisplatin-based chemotherapy, can be achieved since Einhorn and Donohue's landmark 1977 study in TGCT. However, as the severity of accompanying late effects (ototoxicity, neurotoxicity, cardiovascular disease, second malignant neoplasms, nephrotoxicity, and others) has emerged, efforts to deintensity treatment and find alternatives to cisplatin have taken on new urgency. Current innovations include the collaborative design of clinical trials that accrue GCTs across all ages and both sexes, including adolescents (previously on pediatric trials), and OvGCT (previously on gynecologic-only trials). Joint trials accrue larger sample sizes at a faster rate and therefore evaluate new approaches more rapidly. These joint trials also allow for biospecimen collection to further probe GCT etiology and underlying mechanisms of tumor growth, thus providing new therapeutic options. This AYA approach has been fostered by The Malignant Germ Cell International Consortium, which includes over 115 GCT disease experts from pediatric, gynecologic, and genitourinary oncologies in 16 countries. Trials in development incorporate, to our knowledge, for the first time, molecular risk stratification and precision oncology approaches on the basis of specific GCT biology. This collaborative AYA approach pioneering successfully in GCT could serve as a model for impactful research for other AYA cancer types.

Journal of Clinical Oncology

Palliative Care in Adolescents and Young Adults with Cancer

Rosenberg AR

Palliative care (PC) aims to improve quality of life (QOL) for patients with serious illness and their families by recognizing and alleviating the physical, emotional, social, existential, and spiritual suffering of patients and their communities. Because adolescents and young adults (AYAs, age 15-39 years) with cancer commonly report distress across all these domains and because that distress translates to their QOL during and after their cancers, PC is particularly relevant for this population. Here, we review the evidence for PC among AYAs with cancer, including its rationale, gaps, opportunities, and implications for care delivery. For example, nearly 90% of AYAs with cancer report distressing symptoms during their treatment, those who survive report ongoing unmet psychosocial and physical health needs, and those who die from their cancers are highly likely to receive medically intense care that is discordant with their goals and values. AYA communication and decision making can be challenging because of ethical and developmental considerations regarding the patient's autonomy and competing priorities of patients and caregivers. PC interventions (including primary PC delivered by oncologists, routine PC subspecialty care, symptom tracking, advance care planning, and psychosocial programs promoting AYA resilience) are all associated with improved patient-centered outcomes. However, PC is inconsistently integrated into AYA oncology care, and access to PC programs is not equitable; marginalized groups continue to experience poorer outcomes. Ongoing and future research and clinical initiatives must continue to bridge these gaps. Improving the QOL of AYAs with cancer is a shared goal of the larger clinical oncology community, and including PC in AYA cancer care delivery can help attain that goal.

Journal of Clinical Oncology

Quality of End-of-Life Care Among Adolescents and Young Adults with Cancer

Mack JW, Cernik C, Uno H, Fisher L, Cooper RM

Adolescents, young adults with cancer receive limited psychosocial and spiritual support near death.

Journal of the National Cancer Institute

Use of Cancer-Directed Therapy at the End of Life Among Adolescents and Young Adults

Mack JW, Cernik C, Fisher L, Lakin JR, Uno H

BACKGROUND: Adolescents and young adults (AYAs) frequently receive chemotherapy near death. We know less about use of targeted agents and immunotherapy or trends over time.

METHODS: We conducted a retrospective cohort study of 1,836 AYAs with cancer who died between 2009-2019 after receiving care at one of three sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90?days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs.

RESULTS: Over the study period, 35% of AYAs received chemotherapy in the last 90?days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Fifty-six percent received at least one form of systemic cancer-directed therapy in the last 90?days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of AYAs receiving targeted therapy (odds ratio (OR) 1.05 per year of death, 95% confidence interval (CI) 1.02-1.10, P?=?.006), immunotherapy (OR 1.27, 95%CI 1.18-1.38, P<.0001), and any cancer-directed therapy (OR1.04, 95%CI 1.01-1.08, P=.01) in the last 90?days of life increased over time.

CONCLUSIONS: More than half of AYAs receive cancer therapy in the last 90?days of life, and use of novel agents such as targeted therapy and immunotherapy are increasing over time. While some AYAs may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of AYAs approaching death.

JAMA Oncology

Accreditation Standards-An Untapped Lever for Cancer Equity

Erfani P, Uppal N, Lam MB

Over the past 3 decades, cancer mortality rates in the US have declined by 32%, yet significant disparities in cancer outcomes persist. Expansion of insurance coverage, cancer screening, and programs addressing socioeconomic barriers to care have narrowed gaps in outcomes. However, these efforts have yielded inconsistent results given their dependence on government and institutional buy-in. Cancer center accreditation and designation standards could be used as levers to set more consistent baseline standards for cancer care access and equity. Two primary accreditation and designation bodies for cancer care in the US are the Commission on Cancer (CoC) and the National Cancer Institute (NCI). The CoC sets standards for cancer care delivery and quality, monitors treatment patterns and outcomes, and develops educational interventions to improve cancer outcomes. The goals of the NCI Cancer Centers Program are to promote discovery and cancer research. Here, we outline opportunities for these bodies to incorporate health equity benchmarks into existing standards.

JAMA Oncology

Mortality Risks Over 20 Years in Men with Stage I to III Hormone Receptor-Positive Breast Cancer

Hassett MJ, Freedman RA, Tolaney SM, Graham N, Tayob N, Lin NU, Leone JP

IMPORTANCE: In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported.

OBJECTIVE: To report 20-year risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I to III HR+ breast cancer and identify factors associated with late BCSM.

DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study was conducted of men diagnosed with HR+ breast cancer from 1990 to 2008, using population-based data from the Surveillance, Epidemiology, and End Results program. Men diagnosed with stage I to III HR+ breast cancer were included in the analysis. Cumulative incidence function was used to estimate the outcomes of baseline clinicopathologic variables regarding cumulative risk of BCSM and non-BCSM since diagnosis. Smoothed hazard estimates over time were plotted for BCSM. Fine and Gray multivariable regression evaluated the association of preselected variables with BCSM, conditional on having survived 5 years.

MAIN OUTCOME MEASURE: BCSM.

RESULTS: A total of 2836 men with stage I to III HR+ breast cancer were included, with a median follow-up of 15.41 (IQR, 12.08-18.67) years. Median age at diagnosis was 67 (IQR, 57-76) years. The cumulative 20-year risk of BCSM was 12.4% for stage I, 26.2% for stage II, and 46.0% for stage III. Smoothed annual hazard estimates for BCSM revealed an increase in late hazard rates with each incremental node category, reaching a bimodal distribution in N3 and stage III, with each having peaks in hazard rates at 4 and 11 years. Among patients who survived 5 years from diagnosis, the adjusted BCSM risk was higher for those younger than 50 years vs older than 64 years, those with grade II or III/IV vs grade I tumors, and stage II or III vs stage I disease.

CONCLUSIONS AND RELEVANCE: The findings of this study suggest that, in men with stage I to III HR+ breast cancer, the risk of BCSM persists for at least 20 years and depends on traditional clinicopathologic factors, such as age, tumor stage, and tumor grade. Among men with higher stages of disease, the kinetics of the BCSM risk appear different from the risk that has been reported in women.

Annals of Surgical Oncology

ASO Visual Abstract: Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions

Laws A, Leonard S, Stokes S, Vincuilla J, Sharma E, Garber JE, King TA

Antioxidants and Redox Signaling

DAMPening Tumor Immune Escape: The Role of ER Chaperones in Immunogenic Chemotherapy

Cifric S, Folino P, Clericuzio C, Maciel T, Anderson KC, Gulla A

Blood Advances

Five-Year Follow-Up of a Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, and Rituximab as Initial Therapy in CLL

Ahn IE, Ren Y, Zhou Y, Tyekucheva S, Walker HA, Black R, Montegaard J, Jacobson CA, Armand P, Ng SY, Crombie J, Fisher DC, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Brown JR, Davids MS

Blood Advances

Prophylactic Maintenance with Venetoclax/Azacitidine After Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk MDS and AML

Garcia JS, Kim HT, Murdock HM, Ansuinelli M, Brock J, Cutler CS, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro R, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan J, Contreras ME, Fell G, Letai A, Ritz J, Lindsley RC, Soiffer RJ, Antin JH

Bone Marrow Transplantation

Overlap Chronic GVHD is Associated with Adverse Survival Outcomes Compared to Classic Chronic GVHD

Gorfinkel L, Hebert K, Neuberg DS, Bratrude B, Betz K, Yu A, Duncan C, Horan JT, Kean LS

British Journal of Dermatology

Why Do We Distinguish Between Virus-Positive and Virus-Negative Merkel Cell Carcinoma?

Bahar F, DeCaprio JA

Breast

2023 Year in Review: Early Breast Cancer

Nader-Marta G, Partridge AH

Cancer Research Communications

Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer

Goldberg J, Guerriero JL, Gross B, Rahman T, Jeselsohn R, Tolaney SM, Mittendorf EA

Cell Reports

XRN1 Deletion Induces PKR-Dependent Cell Lethality in Interferon-Activated Cancer Cells

Zou T, Zhou M, Gupta A, Zhuang P, Fishbein AR, Wei HY, Capcha-Rodriguez D, Zhang Z, Cherniack AD, Meyerson M

Clinical Cancer Research

PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

Denize T, Jegede OA, Matar S, El Ahmar N, West DJ, Walton E, Bagheri AS, Savla V, Nabil Laimon Y, Braun DA, Burke KP, Catalano PJ, Freeman GJ, McDermott DF, Sharpe AH, Choueiri TK, Signoretti S

Clinical Cancer Research

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-Resistant Estrogen Receptor Positive Breast Cancer

Guarducci C, Nardone A, Russo D, Nagy Z, Heraud C, Grinshpun A, Zhang Q, Cohen Feit G, Feiglin A, Liu W, Hermida-Prado F, Kesten N, Ma W, De O'Donnell M, Naumenko S, Nguyen QD, Huang Y, Bergholz Villafane JS, Zhao JJ, Shapiro GI, Jeselsohn R

Clinical Cancer Research

Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer

Saito S, Kono M, Nguyen HCB, Egloff AM, Lizotte P, Paweletz C, Uppaluri R

Clinical Medicine Insights: Oncology

Breast Cancer in Young Women: Is It Different? A Single-Center Retrospective Cohort Study

Partridge A

Current Oncology Reports

Addressing Residual Disease in HER2-Positive and Triple-Negative Breast Cancer: What Is Next?

Lynce F

Gynecologic Oncology Reports

Combined Aromatase, CDK4/6 and PI3K Blockade Using Letrozole/Abemaciclib/LY3023414 in Endometrial Cancer

Konstantinopoulos PA, Xiong N, Krasner C, Liu JF, Sawyer H, Polak M, Needham H, Geddes M, Koppermann L, Shea M, Castro C, Cheng SC, Matulonis UA, Lee EK

Haematologica

Characterization of Zanubrutinib Safety and Tolerability Profile and Comparison with Ibrutinib Safety Profile in Patients with B-Cell Malignancies: Post-Hoc Analysis of a Large Clinical Trial Safety Database

Brown JR

iScience

Immune-Restoring CAR-T Cells Display Antitumor Activity and Reverse Immunosuppressive TME in a Humanized ccRCC Mouse Model

Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, Marasco WA

Journal of the Academy of Consultation-Liaison Psychiatry

Annual Meeting Content Analysis: Leveraging Annual Meetings to Promote Diversity, Equity, Inclusion, and Belonging in the Academy of Consultation-Liaison Psychiatry

Amonoo HL, Boardman AC, Fernandez-Robles C, Dale C, Mittal LP

Journal of Cell Biology

PC4: A New Regulator of Cyclin D1 Transcript Levels

Sicinski P

Journal of Imaging Informatics in Medicine

Auto-Segmentation of Adult-Type Diffuse Gliomas: Comparison of Transfer Learning-Based Convolutional Neural Network Model vs. Radiologists

Wan Q, Kim J, Huang RY, Reardon D, Young GS, Qin L

Journal of Virology

Inhibition of Human Immunodeficiency Virus (HIV-1) Infectivity by Expression of Poorly or Broadly Neutralizing Antibodies Against Env in Virus-Producing Cells

Wang Q, Zhang S, Nguyen HT, Sodroski J