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An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.

ABSTRACT: Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities.

SUBMITTER: Johnson BE

PROVIDER: S-EPMC8861971 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.

Johnson Brett E BE Creason Allison L AL Stommel Jayne M JM Keck Jamie M JM Parmar Swapnil S Betts Courtney B CB Blucher Aurora A Boniface Christopher C Bucher Elmar E Burlingame Erik E Camp Todd T Chin Koei K Eng Jennifer J Estabrook Joseph J Feiler Heidi S HS Heskett Michael B MB Hu Zhi Z Kolodzie Annette A Kong Ben L BL Labrie Marilyne M Lee Jinho J Leyshock Patrick P Mitri Souraya S Patterson Janice J Riesterer Jessica L JL Sivagnanam Shamilene S Somers Julia J Sudar Damir D Thibault Guillaume G Weeder Benjamin R BR Zheng Christina C Nan Xiaolin X Thompson Reid F RF Heiser Laura M LM Spellman Paul T PT Thomas George G Demir Emek E Chang Young Hwan YH Coussens Lisa M LM Guimaraes Alexander R AR Corless Christopher C Goecks Jeremy J Bergan Raymond R Mitri Zahi Z Mills Gordon B GB Gray Joe W JW

Cell reports. Medicine 20220215 2

Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata t ...[more]

PMID: 35243422

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Project description:BackgroundMetastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood.MethodsVia rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor's evolution at subclonal resolution.ResultsThe most unique, previously unreported aspect of the tumor's evolution that we observed in this patient was the presence of "subclone incubators," defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient's metastases for effective clinical intervention.ConclusionsOur analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

Project description:Multidimensional molecular analysis of tumor tissue intensively over space and time can provide insight into how cancers evolve and escape treatment. Attitudes of participants in such trials have not been assessed. We explored patient views regarding an intensive study incorporating multiple biopsies, multidimensional molecular testing, and drug response predictions that are reported to the oncologist and patient. A structured, self-administered survey was conducted among the first 15 patients enrolled in ITOMIC-001 (Intensive Trial of Omics in Cancer). Patients with metastatic triple-negative breast cancer were accrued at two sites in Washington state. Surveys containing 17 items were administered at enrollment and after the return of results. Surveys explored perceptions regarding risks, personal benefits, benefits to others, uncertainties associated with interpreting complex molecular results, concerns regarding multiple biopsies, and potential loss of confidentiality. At follow-up, three additional unique items explored patient coping. All participants expressed a strong desire for their experiences to benefit others, and all perceived a higher likelihood of deriving benefit than described during detailed consent discussions. Loss of confidentiality ranked lowest among patient concerns. Despite acknowledging uncertainties and risks inherent in complex molecular testing for clinical reporting, participants wanted access to findings in evaluating treatment choices, even if the best available evidence was weak. Follow-up surveys demonstrated relatively little change in attitudes, although concern about study biopsies generally declined. Study participation helped several patients cope better with their disease. In advanced breast cancer, these findings demonstrate the feasibility of engaging motivated patients in trials that navigate the uncertainties associated with intensive spatial and longitudinal multidimensional molecular testing for the purpose of advancing precision medicine.

Dataset Information

An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.

Publications

An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.

Similar Datasets

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