Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

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Abstract

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer ( KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 22 November 2020

Publication date Collection: November 2020

Volume: 21

Issue: 22

Electronic Location Identifier: 8841

Affiliations

[1 ]Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; chiara.bazzichetto@ 123456ifo.gov.it (C.B.); vanja.vaccaro@ 123456ifo.gov.it (V.V.); italia.falcone@ 123456ifo.gov.it (I.F.); gianluigi.ferretti@ 123456ifo.gov.it (G.F.); francesco.cognetti@ 123456ifo.gov.it (F.C.)

[2 ]Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; claudio.luchini@ 123456univr.it (C.L.); i.dicello@ 123456yahoo.com (I.D.C.); paolamattiolo@ 123456gmail.com (P.M.)

[3 ]Department ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy; aldo.scarpa@ 123456univr.it

[4 ]Division of Oncology, University of Verona, 37126 Verona, Italy; michele.milella@ 123456univr.it

Author notes

[* ]Correspondence: fabiana.conciatori@ 123456ifo.gov.it ; Tel.: +39-06-52665185

[†]

These authors contributed equally to this work.

Author information

Chiara Bazzichetto https://orcid.org/0000-0002-1648-3700

Claudio Luchini https://orcid.org/0000-0003-4901-4908

Fabiana Conciatori https://orcid.org/0000-0002-8579-5222

Italia Falcone https://orcid.org/0000-0003-2796-0792

Gianluigi Ferretti https://orcid.org/0000-0002-2271-6427

Aldo Scarpa https://orcid.org/0000-0003-1678-739X

Article

Publisher ID: ijms-21-08841

DOI: 10.3390/ijms21228841

PMC ID: 7700259

PubMed ID: 33266496

SO-VID: ef1b7a3b-bae8-44f5-beee-c974fde18424

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

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Abstract

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Higher order chromatin architecture

Most cited references 182

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Cancer statistics, 2019

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

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