genomic medicine for oncology practitioners | genentech forum · 3/12/2020 · precision medicine...

Genomic Medicine for Oncology Practitioners

The information is the property of Genentech, is intended for educational use, and may not be repurposed.© 2020 Genentech USA, Inc. All rights reserved. M-US-00004226(v1.0).

Table of Contents

§ Precision Medicine

§ Biomarkers

§ Complexities in the Interpretation of Results in the Practice of Precision Oncology

§ Clinical Trials in Precision Medicine

§ Conclusions and Key Takeaways

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2The information is the property of Genentech, is intended for educational use, and may not be repurposed.© 2020 Genentech USA, Inc. All rights reserved. M-US-00004226(v1.0).

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Precision Medicine§ The following section focuses on the role of precision medicine in the care of patients with

cancer, including:

− How precision medicine contributes to individualized patient care

− The contribution of the Human Genome Project to the advent of precision medicine

− The goals of precision medicine in patient care


Precision Medicine Defined

1. Morganti S, et al. Crit Rev Oncol Hematol. 2019;133:171-182. 2. Le Tourneau C, et al. J Natl Cancer Inst. 2015;108(4). 3. Laes J-F, et al. Oncotarget. 2018;9:20282-20293.

§ Genetic alterations that accumulate over time are the root cause of tumorigenesis1

§ The recognition that cancer is driven by these types of mutations that are either inherited or acquired through DNA replication errors or environmental exposure to carcinogens has led to a paradigmatic shift in how medicine is practiced1

§ According to the National Cancer Institute, precision (personalized) medicine2:

− Uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease

§ Cytotoxic agents are non-specific in their mode of action to slow or destroy rapidly dividing cells3

− In destroying the tumor, normal cell function may be adversely impacted

§ The value of precision medicine is the ability to select the most effective targeted treatment for a given patient based on the most comprehensive and relevant information available about the driver mutation2


Precision Medicine: Why now?

National Institute of Health. The Precision Medicine Initiative. https://www.nih.gov/news-events/multimedia-nih-framework-points-way-forward-building-national-large-scale-research-cohort#infographic. Accessed March 11, 2020.

The time is right because of:

Sequencing of the human

genome

Improved technologies for

biomedical analysis

New tools for using large

datasets


The Future of Precision Medicine

Image is for illustrative purposes only. 1. What is personalised healthcare all about? Roche. https://www.roche.com/about/priorities/personalised_healthcare/what_is_phc.htm. Accessed March 11, 2020. 2. Personalised Healthcare (PHC). Roche. https://www.roche.ie/en/about/personalised-healthcare.html. Accessed March 25, 2020. 3. Precision medicine in cancer treatment. NCI. https://www.cancer.gov/about-cancer/treatment/types/precision-medicine Accessed March 11, 2020. 4. Vijayaraghavan A, et al. Int J Cancer. 2012;131:438–445.5. Garrison LP Jr, et al. Value Health. 2015;18:541–546.

Personalized Healthcare (PHC) is Evolving Toward Individualized Care1-3

Accurate biomarker testing may help reduce healthcare costs4,5


The Foundation of Precision Medicine

1. Laes J-F, et al. Oncotarget. 2018;9:20282-20293. 2. Goldman AD, et al. PLoS Genet. 2016;12:e1006181. 3. Human genome project results. National Human Genome Research Institute. https://www.genome.gov/human-genome-project/results. Accessed March 11, 2020. 4. Kittaneh M, et al. Biomark Cancer. 2013;5:61-70. 5. Sepulveda AR, et al. J Mol Diagn. 2017;19:187-225.

§ Foundation of personalized medicine − Analysis of patients’ genomic information to inform

disease management1

§ “Genomics” as a term− Popularized following the publication of the

complete human genome in 20032,3

§ The Genome3

− Entirety of an individual’s genes− Interactions between genes− Interactions between genes and the environment

§ Information used in clinical care to4,5:− Predict a person’s risk of cancer or response to a

given treatment− Prognosticate likely outcomes for a given disease

or cancer risk− Discover novel therapies

From gene to genome. Image courtesy of Wikimedia Commons.


Goals of Precision Medicine

1. Morganti S, et al. Crit Rev Oncol Hematol. 2019;133:171-182. 2. Beckman JS, et al. Genome Med. 2016;8:134.

§ Genomic testing provides the opportunity to stratify patients based on their molecular profile1

− Mutations in variety of tumor types create genetic signature specific for a given patient− Therapeutic modalities targeting specific mutations render these signatures actionable

§ Precision medicine has the potential to enable2:− Detection of disease risk before any evidence of disease

− Delay of disease onset− Earlier detection of symptomatic disease− More rapid initiation of treatment− Delivery of treatment specifically targeted to etiology of disease− Improved monitoring of the disease course

§ Transformational shift in the practice of medicine2

− No longer an organ-based approach− Rather, an all-inclusive, systemic assessment of health

− Changing emphasis from treatment to prevention and from disease to wellness


§ Precision medicine uses a person’s genetic code to help prevent, diagnose, and treat disease– As a result, it is transforming the practice of oncology

LeTourneau C, et al. J Natl Cancer Inst. 2015;108.

Precision Medicine: Key Takeaways


Biomarkers§ The following section focuses on ways to monitor molecular signatures of patient tumors as an

integral part of cancer care, including:

− Existing and emerging biomarkers in cancer care

− Biomarker testing methods

− Workflow of genetic testing


Biomarkers: A Look Into the Future of a Patient’s Care

BRCA, BReast CAncer gene; HER2, human epidermal growth factor receptor 2.1. Oldenhuis CNAM, et al. Eur J Canc. 2008;44:946–953. 2. Goossens N, et al. Transl Cancer Res. 2015;4:256–269.

Identify whether patient has a specific disease2

Multigene stool DNA for colorectal cancer2

Diagnostic

Inform about overallcancer outcomes1

BRCA in breast cancer2

Prognostic

Estimate response to specific therapy2

HER2 in multiple tumor types2

Predictive

Types of biomarkers1,2

Examples Examples

§ Responses to anti-cancer therapies can vary between individuals1

§ Biomarkers characterize the disease on a molecular level2

§ Biomarkers can identify patients who are more likely to respond to treatment2


Emerging Biomarkers and Techniques for Identifying Driver Mutations

CISH, chromogenic in situ hybridization; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; NGS, next-generation sequencing; RT-PCR, reverse transcriptase polymerase chain reaction.1. Melendez B, et al. Trans Lung Cancer Res. 2018;7:661–667. 2. Chalmers ZR, et al. Genome Med. 2017;9:34. 3. Nojadeh JN, et al. EXCLI Journal. 2018;17:159–168. 4. Reichert RR, et al. JAMA Oncol. 2019;5(4):478-479. 5. FDA's List of Cleared or Approved Companion Diagnostics Devices. https://www.fda.gov/media/119249/download Accessed March 11, 2020. 6. Teutsch SM, et al. Genet Med. 2009;11:3-14. 7. Kerr KM, et al. Ann Oncol. 2014;25:1681-90.

Tumor mutational burden: emerging predictive biomarker

for immunotherapy1,2

Total number of mutations per coding area of tumor genome (eg, due to exposure to mutagen

like in melanoma, lung cancer)Can increase x 2.5 between childhood and 90 years of age, with no difference between sexes

Molecular phenotype that occurs due to defects in DNA mismatch repair system

Microsatellite Instability: another marker of mutational

risk in the genome2-4

5 IHC image provided by Leo A. Niemeier, MD, and FISH image provided by Hadi Yaziji, MD.

IHC ISH (eg, FISH, CISH) Sequencing (eg, NGS) RT-PCR

§ Importance of analytic/clinical validity and clinical utility of biomarker tests6

§ Differences in analytic sensitivities, turnaround times, and costs– FISH can be expensive and hard to interpret7– IHC can be used as a less expensive “pre-test” for confirmation with FISH7

– Cost of high-throughput NGS may be lower than panel of tests but platforms lack standardization7


Liquid Biopsy: Detecting Cancer via Blood Draw

Cell-free circulating tumor DNA (ctDNA)§ Minimally invasive procedure1,2

§ Valid alternative or follow-up modality1

− ~20% of biopsies from patients with NSCLC do not yield enough tissue to perform molecular analysis1

§ Detects DNA fragments released into blood from apoptotic tumor cells1,2

§ Clinically relevant tool to detect molecular changes that drive disease progression and treatment resistance1,2

§ May be used for detecting minimal residual disease and may help improve diagnostics and prognostication3,4

– Lung cancer: ctDNA may help detect early disease; amounts may increase further with cancer stage advances and tumor size3

– Breast cancer: can track mutation status over disease course, help monitor recurrence, and may detect relapse3

– Colon cancer (stage II): ctDNA in post-surgical plasma samples was able to predict very high risk of radiologic recurrence after adjuvant CT + resection4

Image from the National Cancer Institute, 2016. Courtesy of Wikimedia Commons.

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CT, chemotherapy; NSCLC, non-small cell lung cancer.1. Gagan J, et al. Genome Med. 2015;7:80; 2. Tan DSW, et al. J Thoracic Onc. 2016;11:946-963. 3. Chae YK and Oh MS. J Thorac Oncol. 2019;14(1):16-24. 4. Tie J et al. Sci Transl Med. 2016; 8(346): 346ra92. doi:10.1126/scitranslmed.aaf6219.


A Simplified Genomic Test Workflow Model

EMR, electronic medical record; Tx, therapy.1. Cutting EM, et al. AMIA Annu Symp Proc. 2015:466-474. 2. Gagan J, et al. Genome Med. 2015;7:80. 3. Association of Public Health Laboratories. Next-generation Sequencing Implementation Guide. 2016.

§ Regardless of the type of assay performed, getting test results to the clinical care provider can be complex due to1:− Time-sensitive steps− Gaps in the communication interface between the patient’s healthcare system EMR and the external laboratory analyzing the

sample and delivering the report§ Creating workflow models from patient diagnosis to initiation of treatment and follow-up monitoring for each test helps

standardize the process and identify gaps, deficiencies, and opportunities for improvement of those processes1-3:

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Concurrent steps

Identify patient & tumor type

1

Identify biomarker

to be tested

2

Order appropriate

assay

3

Perform assay

4

Assay result verified & approved

5

Upload results into EMRs

6

Draft letter to care team

7

If actionable, call physician listed

on report

8

Initiate targeted Tx or clinical trial; avoid

unnecessary Tx

9

Monitor outcomes & resistance mutations

10

Monitor patient response

11

Adjust Tx as needed

12

Continue monitoring progress/ development

of resistance

13

Time variable between systems (hours to days)

14

Particularly time-sensitive steps


§ Biomarkers can provide information about patient diagnosis, prognosis, and relevant predictive outcomes1,2– Molecular characterization of tumors can help identify patients more likely to respond to a specific

treatment§ Tumor mutational burden is an emerging biomarker for potential responsiveness

to immunotherapy3– In certain types of cancers (eg, lung, melanoma), greater exposure to mutagens is known to be

associated with higher mutational burden– Between age 10 and age 90, tumor mutational burden increases nearly 2.5-fold

§ There are several methods for identifying tumor mutation drivers, each with its respective advantages and disadvantages4,5– Workflows can be complex6

1. de Mello RA, et al. Pharmacogenomics. 2013;14:1765-1777. 2. Goossens N, et al. Transl Cancer Res. 2015;4:256-269. 3. Chalmers ZR, et al. Genome Med. 2017;9:34. 4. Khoo C, et al. Transl Lung Cancer Res. 2015;4:126-41. 5. Kerr KM, et al. Ann Oncol. 2014;25:1681-1690. 6. Cutting EM, et al. AMIA Annu Symp Proc. 2015;466-474.

Biomarkers: Key Takeaways


Complexities in the Interpretation of Results in the Practice of Precision Oncology

§ The following section focuses on considerations regarding the interpretation of results in the practice of precision oncology, including:

− Tumor heterogeneity

− Tumor evolution


Tumor Genetic Diversity

Liu J, et al. Exp Mol Med. 2018;50:e416.

§ Genomic analyses can reveal complexities in the tumor mutational landscape

§ Understanding the link between intertumor and intratumor heterogeneity may improve tumor subclassification and treatment stratification

§ Resistant clones may be selected and expanded through tumor evolution

§ Intertumor heterogeneity− Tumors may differ between patients due to altered genotypes and

phenotypes− Influenced by etiology and environment

§ Intratumor heterogeneity− Differences within a tumor due to genomic and biologic variations− Influenced by microenvironment− Can contribute to drug resistance and tumor relapse following therapy

Intertumor heterogeneity

Intratumor heterogeneity

Perform biopsies

Subclone 1

Subclone 2

Subclone 3

Subclone 4

Image adapted from Liu J, et al. Exp Mol Med. 2018;50:e416.


§ The utility of tumor marker retesting can be influenced by tumor heterogeneity1

− Consider the value of retesting (ie, if a significant survival benefit would be conferred by a targeted therapy)1

− A false negative can delay treatment and impact outcomes2

− Discordance between core biopsy and surgical resection can be observed3

− Neoadjuvant therapy can alter target biomarker expression4

§ In grade 3 breast carcinoma, the rate of clinically significant HER2 status discordance between core biopsy and surgical specimens is low5

− Retesting in surgical specimens is supported in patients with HER2-negative core biopsies1,5

How Tumor Heterogeneity Impacts Biomarker Testing

1. Golorgsky RC, et al. Perm J. 2019;23:18-088. 2. Niu J, et al. J Gastrointest Oncol. 2012;3:358–361. 3. Robertson S, et al. Breast Cancer Res Treat. 2019;174:795-805. 4. Niikura N, et al. Ann Oncol. 2016;27:480-487. 5. Wolff AC, et al. J Clin Oncol. 2018;36:2105-2122.

Homogenous biomarker-negative

tumor cells

Homogenous biomarker-positive

tumor cells

Heterogenous mixed biomarker-positive

tumor cells

Heterogenous clustered biomarker-positive

tumor cells

Image adapted from Nitta H, et al. Pathol Int. 2016;66:313-24.


How Tumor Heterogeneity Impacts Biomarker Testing (Cont’d)HER2 Biomarker Testing Considerations

§ Esophageal Carcinoma: A “False-negative” Case Study1

− A patient with aggressive esophageal carcinoma originally tested HER2-negative in initial biopsy with a follow-up positive test

− Retest of the original biopsy indicated tumor heterogeneity

ASCO, American Society of Clinical Oncology; ASCP, American Society for Clinical Pathology; CAP, College of American Pathoologists; HER2, human epidermal growth factor receptor 2. 1. Niu J, et al. J Gastrointest Oncol. 2012;3:358-361. 2. Bartley AN, et al. J Clin Oncol. 2017;35:446-464. 3. Niikura N, et al. Ann Oncol. 2016;27:480-487.

The CAP/ASCP/ASCO guidelines recommend that patients with advanced gastroesophageal adenocarcinoma who are candidates for HER2-targeted therapy be assessed for HER2 status prior to targeted therapy initiation, with retesting allowed if there is no documented HER2-positive result or if inadequate specimens were tested2

§ HER2-positive Breast Cancer: Loss of Biomarker Status3

− In a retrospective study of the clinical records of 2811 patients with HER2-positive breast cancer before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 240 (3.4%) of the 9476 patients with HER2-negative tumors before treatment were HER2-positive after treatment

Loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer, thus supporting the need for retesting after adjuvant therapy


§ Various aspects of the molecular characteristics of a patient’s tumor can affect the interpretation of biomarker testing results in the practice of precision oncology, including: – Tumor heterogeneity– Tumor evolution

Wheeler HE, et al. Nat Rev Genet. 2013;14:23-34.

Complexities in the Interpretation of Results in the Practice of Precision Oncology: Key Takeaways


Clinical Trials in Precision Medicine§ The following section presents an overview of how trial designs allow scientists to leverage

precision medicine approaches in clinical research, including:

− Umbrella trials

− Adaptive design trials

− Basket trials


Umbrella Trials

1. Clinical trial design and methodology. American Society for Clinical Oncology. https://www.asco.org/research-guidelines/clinical-trials/clinical-trial-resources/clinical-trial-design-methodology. Accessed March 11, 2020. 2. Woodcock J, et al. N Engl J Med. 2017; 377:62-70. 3. Garralda E, et al. Mol Oncol. 2019;13:549–557.

One tumor type2,3Different molecular alterations ( )2,3

Different targeted therapies2,3

Test drug 1 Test drug 2 Test drug 3

Molecular alterations in specific arms within one trial1

§ Biomarkers are now being used as selection criteria for clinical trials that evaluate the safety and efficacy of targeted therapies1-3

§ Master protocol that will test different therapies in the same tumor type, with stratification based on the specific molecular alterations2,3

– Multiple targeted therapies are perpetually tested in the context of a single disease, with therapies allowed to enter or leave the platform based on an algorithm2

§ In an umbrella trial, patients are screened for a specific molecular alteration and then assigned to a specific treatment arm1,2

Umbrella Trials


Design

Conduct

Analyze

Traditional fixed-sample design Adaptive design

Assess

Modify

Design

Conduct

Analyze

Adaptive Design

Pallman P, et al. BMC Med. 2018;16:29.

§ Leverage accumulating data (eg, interim analyses) in a trial to modify the trial’s course in accordance with pre-specified criteria, maintaining the validity and integrity of the trial

§ Are applicable to all phases of clinical trials

§ May be more efficient, informative, and ethical than trials with a traditional fixed design and make better use of resources

Adaptive Designs


Basket Trials Vary in Complexity: Simple

1. Garralda E, et al. Molecular Oncology. 2019;13:549-557. 2. American Society for Clinical Oncology. https://www.asco.org/research-guidelines/clinical-trials/clinical-trial-resources/clinical-trial-design-methodology. Accessed on March 12, 2020. 3. Cunanan KM, et al. J Clin Oncol. 2017;35(3):271–273.

Multiple tumor types1A single molecular alteration ( )1

One targeted therapy1

Test drug

Disease-specific baskets3

§ A basket trial differs from an umbrella trial in that multiple tumor types may be included as long as they all harbor a single molecular alteration1,2

§ However, basket trials vary in complexity3

§ The simplest design includes one drug targeting a single molecular alteration in a variety of tumor types (ie disease-specific baskets3

Simple Basket Trials


Basket Trials Vary in Complexity: Complex

Cunanan KM, et al. J Clin Oncol. 2017;35:271-273.

Multiple types of cancer≥ 1 molecular alterations ( )

One targeted therapy

Disease mutation-specific baskets1

§ Basket trials vary in complexity

§ A complex basket trial design can include a single agent targeting more than one molecular alteration in multiple tumor types, with the baskets reflecting both diseases and targets (ie, disease-mutation-specific baskets)

Complex Basket Trials

Test drug


Basket Trials Vary in Complexity: More Complex

Cunanan KM, et al. J Clin Oncol. 2017;35:271-273.

§ Basket trials vary in complexity§ A complex basket trial design can

include a single agent targeting more than one molecular alteration in multiple tumor types, with the baskets reflecting both diseases and targets (ie, disease-mutation-specific baskets)

§ More complex designs include multiple therapies targeted at a number of biomarkers and tumor types, reflecting disease-drug-mutation-specific baskets

More Complex Basket Trials

Multiple tumor types≥ 1 molecular alterations ( )

Several targeted therapies

Disease and drug-mutation-specific baskets1

Test drug 1

Test drug 3Test drug 2

Test drug 4


There are several types of clinical trials in precision medicine:§ Umbrella trials1,2

– A master protocol that tests different therapies in the same tumor type and stratifies based on specific molecular alterations

§ Adaptive designs3

– Leverage interim analyses to modify the trial’s course in accordance with pre-specified criteria, maintaining the validity and integrity of the trial

§ Basket trials4

– Vary in complexity, from the simplest design of disease-specific baskets to more complex designs of disease-mutation-specific baskets and disease-drug-mutation-specific baskets

1. Garralda E, et al. Mol Oncol. 2019;13:549–557. 2. Woodcock J, et al. N Engl J Med. 2017; 377:62-70. 3. Pallman P, et al. BMC Med. 2018;16:293. 4. Cunanan KM, et al. J Clin Oncol. 2017;35:271-273.

Clinical Trials in Precision Medicine: Key Takeaways


Conclusions

Improving the knowledge and understanding of precision medicine among practitioners is essential for cancer care

28

The integration of biomarker testing to the precision oncology workflow supports the personalization of cancer care to individual patients

Decisions regarding clinical trial designs allow investigatorsto help address unmet needs in the treatment landscape


Additional Educational Resources*


*Genentech does not endorse any of the resources provided on this slide.

Genomic Medicine for Oncology Practitioners


genomic medicine for oncology practitioners | genentech forum · 3/12/2020 · precision medicine...

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