Precision Cancer Medicine and Profile at Dana-Farber
More Than a Decade of Precision Cancer Medicine
Precision (also called personalized) cancer medicine is guided by the specific biology of each patient's cancer – the type and subtype of the cancer, its set of genetic abnormalities, its vulnerability to certain therapies, including immunotherapy, and the patient's overall health. It recognizes that each patient – and each patient's disease – is unique, and that treatment is most effective when geared to these distinctive features.
A critical part of precision cancer medicine at Dana-Farber involves an initiative called Profile, which identifies the genetic mutations and other alterations within a patient's tumor cells to create a "tumor profile." Today, drugs are available that precisely target many of these abnormalities. These drugs enable doctors to strike at cancer's fundamental roots in the genome, in ways that often produce milder side effects than traditional therapies.
About Precision Cancer Medicine
What is precision cancer medicine?
Precision cancer medicine is an evolving approach to cancer care that aims to harness knowledge about the origin and development of cancer in order to target therapy more precisely. We now know that most, if not all, cancer results from abnormal genes or gene regulation. The cause of these changes can be environmental, such as smoking; spontaneous, such as changes in genes; or genetic alterations that are inherited.
Clinicians at Dana-Farber Brigham Cancer Center are armed with specialized tests that create a personalized "tumor profile" of key genetic changes in each patient's cancer. This can help physicians more accurately diagnose the subtype of a patient's cancer, predict its behavior, and select precisely targeted treatments. In many cases, if we know which genes are altered in any given cancer, we can give a drug that specifically blocks that gene (or the consequences of that gene), potentially producing less-severe side effects than traditional therapies.
How does precision cancer medicine work?
Standard chemotherapy typically destroys rapidly dividing cells, normal and cancerous, in a wide range of tissues, often causing side effects like nausea, mouth sores, and hair loss. By contrast, precision cancer medicine uses targeted therapies engineered to attack tumor cells with specific abnormalities, while leaving normal cells largely unharmed. Some agents are designed to strike directly at cells with specific genetic changes that drive tumors' development and survival, or to inhibit overactive signaling pathways that allow cancer cells to grow and divide uncontrollably. Other treatments enlist the immune system to identify and fight the cancer cells.
Why is precision cancer medicine important?
Each person is unique, and so is each person's cancer. Precision cancer medicine is based on the premise that cancer treatment can be tailored to the genetic makeup of each patient's cancer cells, and to the patient's physiology and medical history.
By studying the cancers of thousands of patients at Dana-Farber Brigham Cancer Center and Dana-Farber/Boston Children's Cancer and Blood Disorders Center, researchers and clinicians are developing a deep understanding of the genomic and biologic factors that drive cancer growth – and are using this knowledge to develop better therapies. We have already identified many genetic mutations in cancer cells that are potential targets for therapy, and are working on identifying still more. And we are working closely with pharmaceutical companies to develop and test potential drugs that strike directly at these mutations.
The Future of Precision Cancer Medicine
As scientific research and computational analysis deepen our understanding of cell biology, we are moving toward the promise of precision cancer medicine. Using next-generation DNA sequencing to thoroughly scan the cancer genome – and large, data-intensive research projects like Profile (described below) to better understand the disposition and behavior of cancer cells – the team at Dana-Farber Brigham Cancer Center is continuing to improve targeted treatments for cancer patients.
In 2011, Dana-Farber scientists launched Profile, one of the nation's most comprehensive personalized cancer medicine initiatives. By analyzing tumor tissue from patients at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Boston Children's Hospital, the Profile project has created one of the world's largest databases of the genetic abnormalities that drive the development of tumors. Researchers can use this information to learn more about the basic biology of cancer and develop drugs against specific molecular targets in cancer cells.
Profile aims to detect a comprehensive set of cancer-related genetic alterations in tumors and non-tumor tissue – information that can help doctors identify targeted therapies that are most likely to benefit individual patients. This database, derived from a very large number of patients and linked to clinical information, makes Profile a powerful tool for discovery and precision cancer medicine.
This database, which adheres to emerging information technology standards, also supports proposals for new research studies and clinical trials. Dana-Farber is a flagship member of Project GENIE, an American Association for Cancer Research initiative that aims to share genomic data internationally across academic cancer centers, with a goal of furthering research and enabling new discoveries. GENIE recently announced the milestone of 100,000 tumor profiles in a database – the largest collection ever assembled.
As part of Profile, more than 100,000 patients have consented to have their tumor tissue analyzed for the presence of genetic mutations and other cancer-related DNA abnormalities. In the past 10 years, Profile has completed more than 50,000 genetic profiles of patients' tumors – reading the genetic code of over 400 genes in each tumor sample. These genes were chosen because they're known to be involved in a variety of cancers and may indicate which therapies are likely to work best for individual patients. The test, called OncoPanel, is performed at the Center for Advanced Molecular Diagnostics, a CLIA-certified laboratory in the Department of Pathology at Brigham and Women's Hospital.
"Genetic profiling" tests are performed on samples of solid tumors, bone marrow, or blood to identify the specific DNA alterations underlying a patient's cancer. More than a decade of research has enabled scientists to identify hundreds of genetic alterations that contribute to cancer – not only mutations, copy number changes, and structural rearrangements in the tumor genome, but also newer signatures like mismatch repair deficiency and mutational burden (the number of mutations within tumor cells). Many of these features indicate whether a cancer is likely to respond to specific treatments, including immunotherapy.
Non-tumor (Germline) Testing
In more recent years, Profile has expanded to include testing for inherited (germline) mutations that may indicate whether an individual and close relatives are at increased risk for certain cancers. This type of testing can also guide treatment in some cases. All patients are now eligible for tests that compare inherited mutations with mutations found in tumor cells. This information can be used to identify which genes are driving the cancer's growth.
A History of Genetic Discoveries
Profile is part of a broader goal at Dana-Farber to advance the field of targeted therapy for cancer. For well over a decade, our scientists and physicians have been at the forefront of efforts to identify potential therapeutic targets in tumor cells and develop and test drugs capable of disabling them. Institute researchers have made key discoveries regarding the role of the EGFR and ALK genes in lung cancer, as well as KRAS, BRAF, and PI3KCA in colorectal cancer – all of which are prime targets for therapy.
Our researchers are also exploring novel mechanisms to genomically profile very small amounts of tumor material, as well as less invasive ways to detect clinically important alterations ("liquid biopsies").
Selected Dana-Farber Precision Cancer Medicine Discoveries
Antibiotic Novobiocin found to kill tumor cells with DNA-repair glitch (D'Andrea, Nature Cancer, 6/17/21)
New immunotherapy target discovered for malignant brain tumors (Wucherpfennig, Cell, 2/15/21)
Immunotherapy – targeted drug combination improves survival in advanced kidney cancer (Choueiri, NEJM, 2/13/21)
Personalized vaccine produces long-lasting anti-tumor response in patients with melanoma, study shows (Wu, Nature Medicine, 1/21/21)
Native American ancestry associated with increased mutations in EGFR gene among Latin American patients with lung cancer (Meyerson, Cancer Discovery, 12/2/20)
CAR T-cell therapy found highly effective in patients with high-risk non-Hodgkin lymphoma (Jacobson, ASH, 12/5/20)
Prostate cancer metastasis linked to revival of dormant molecular program (Freedman, Nature Genetics, 7/20/20)
New technique may quickly and accurately predict effective therapies in solid tumors (Letai, Bhola, Science Signaling, 6/16/20)
Scientists identify factors for predicting which patients with ovarian cancer won’t benefit from immunotherapy-PARP inhibitor combination (Konstantinopoulos, D'Andrea, Nature Communications, 3/19/20)
Researchers describe recently discovered condition involving numerous gastrointestinal polyps in childhood cancer survivors (Biller, Yurgelun, Cancer Prevention Research, 2/12/20)
Identifying More Pancreatic Cancer Gene Mutations With Mandatory Genetic Testing, Counseling (Yurgelun, CGA, 11/5/19)
Cause of drug resistance in a type of intestinal tumors identified (Demetri, Nature, 10/17/19)
New blood test capable of detecting multiple types of cancer (Oxnard, ESMO, 9/28/19)
Study shows benefit of PARP inhibitor for some ovarian cancer patients (Matulonis, Journal of Clinical Oncology, 9/16/19)
“Stapled” antimicrobial peptides could combat antibiotic resistance (Walensky, Nature Biotechnology, 8/19/19)
Inherited pancreatic cancer risk mutation identified (Nissim, Nature Genetics, 8/12/19)
Discovery of pancreatic neuroendocrine subtypes could help predict likelihood of recurrence (Shivdasani, Nature Medicine, 7/2/19)
Scientists identify genes tied to increased risk of ovarian cancer (Gusev, Nature Genetics, 5/2/19)
Study of genomic changes in multiple myeloma may lead to new approaches to treating early, smoldering myeloma (Munshi, Nature Communications, 8/22/18)
Study finds inherited gene variants in 10 percent of pancreatic cancer patients (Yurgelun, Genetics in Medicine Today, 7/2/18)
Comprehensive map of altered gene pathways in dozens of cancer types will guide research in precision cancer medicine (Cancer Genome Atlas, 4/5/18)
Genomic analysis unravels complexities of the most common form of lymphoma and enables personalized treatment (Shipp, Nature Medicine, 4/30/18)
Researchers release first draft of a genome-wide cancer dependency map (Hahn, Cell, 7/27/17)
Targeted drug shows promise in rare advanced kidney cancer (Choueiri, JCO, 6/23/17)
Drug combination shows benefit in RAS-driven cancers (Shapiro, AACR, 4/3/17)
Landscape of Genomic Alterations in Pituitary Adenomas. Clin Cancer Res. 2017 Apr 1;23(7):1841-1851. PMID:27707790
Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors. Neuro Oncol. 2017 Jan 19. PMID: 28104717
Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight. 2016 Nov 17;1(19):e87062. PMID:27882345
Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2016 Jun 15;22(12):2939-49. PMID:26763254
KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung. J Thorac Oncol. 2016 Apr;11(4):496-503. PMID:26829311
Multicenter Feasibility Study of Tumor Molecular Profiling to Inform Therapeutic Decisions in Advanced Pediatric Solid Tumors: The Individualized Cancer Therapy (iCat) Study. JAMA Oncol. 2016 Jan 28. PMID:26822149
Refractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing. Exp Hematol Oncol. 2015 Oct 8;4:30. PMID:26457233
SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas Cancer Cell. 2013 June 10; 23(6):826-838
Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia Cell. 2013 February 14; 152(4):714–726
Sequence analysis of mutations and translocations across breast cancer subtypes Nature. 2012 June 21; 482(7403):405-409
EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer. Cancer Cytopathol. 2009 Feb 25;117(1):67-72
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693-1703
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010 Jan 19;17(1):77-88
Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. Journal of Clinical Oncology. (JCO June 1, 2010 vol. 28 no. 16 2698-2704
Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010 May 11;102(10):1495-502
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009 Dec 24;462(7276):1070-4
Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug 4;101(3): 465-72
Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008 Oct 16;455(7215):975-8
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-500