genetics in cancer diagnosis and treatment

Genetics in Cancer Diagnosis and Treatment44th Semi-Annual Fall 2020 Temple University Family Medicine Review

Kara N. Maxwell, MD, PhDAssistant ProfessorDept of Medicine, Dept of GeneticsCancer Risk Evaluation ProgramPenn Medicine

Conflicts of Interest

I have no conflicts of interest to reportI do not consult for nor recommend any specific genetic testing

company discussed in this presentation

Genetics in Cancer Diagnosis and Treatment

Germline Cancer Genetics• Review of major cancer predisposition syndromes• Cancer risks associated with inherited mutations• Medical management for carriers• Germline Genetic Testing in 2020

Somatic Cancer Genetics• Treatment implications of genetic testing• Somatic Genetic Testing in 2020

Some terms Germline cancer risk mutations - mutations or set of

mutations in all cells from birth, inherited in families that lead to increased risk of development of cancer

• Relative risk – the fold risk increase associated with an inherited mutation over the risk of the cancer in the general population

• Absolute risk – the absolute risk of cancer associated with an inherited mutation (e.g. may be expressed in 5-year, 10-year or lifetime risk of a cancer)

Somatic alterations – acquired mutations in a tumor that may or may not be associated with development and progression of cancer

• Targetable or “Driver” mutations – acquired mutations in a tumor that drive the tumor’s growth and may lead to a response to therapy

• Passenger mutations – acquired mutations in a tumor that likely are not involved in tumor formation and are a result of the oncogenic process

“Germline” or “constitutional”

genetic changes that lead to cancer predisposition

e.gBRCA1, BRCA2

“Somatic” or “driver” changes that lead to cancer progression

e.gGain of HER2

Germline Cancer Genetics

Review of cancer predisposition



Inherited (germline) mutations in a number of tumor suppressor genes lead to autosomal dominant inherited cancer susceptibility

Autosomal Dominant Cancer syndromes 101

Example of a typical BRCA2 family

Examples of cancer predisposition syndromes with autosomal dominant inheritance

Gene(s) Syndrome Cancers

Most common referrals to Cancer Genetics ProgramsBRCA1 Hereditary breast-ovarian cancer syndrome Breast, ovarian

BRCA2 Hereditary breast-ovarian cancer syndrome Breast, ovarian, pancreatic, melanoma, male breast cancer

MLH1, MSH2, MSH6, PMS2

Lynch syndrome (Hereditary nonpolyposiscolon cancer - HNPCC)

Colon, endometrial, ovarian, liver, biliary, upper GI, pancreatic, brain,

urinary tractRare but important high risk cancer syndromes

TP53 Li-Fraumeni syndrome (LFS) sarcomas, osteosarcomas, leukemia, colon, adrenal, brain

CDH1 Hereditary diffuse gastric cancer syndrome diffuse gastric cancer

PTEN Cowden syndrome endometrial, thyroid, brain

Polyposis syndromes

APC Familial adenomatous polyposis (FAP) Colon, upper GI, pancreaticthyroid, brain

BMPR1A Juvenile polyposis syndrome Colon, gastric

STK11 Peutz-Jeghers syndromeColon, gastric, pancreatic, small intestine,

ovarian, cervical, testicular, lung

Rarer autosomal dominant inherited cancer predisposition syndromes

Gene(s) Syndrome Cancers

Endocrine and Renal

MEN1, RET Multiple endocrine neoplasia type 1,2a/b Pituitary, PNET, carcinoids (1)medullary thyroid, pheo (2)

VHL Von Hippel-Lindau syndrome PNET, pheo, clear cell RCC

FH Hereditary leiomyomatosis and renal cell cancer (HLRCC)

cutaneous leiomyomas, uterine leiomyomata (fibroids), and type 2

papillary RCC

FLCN Birt-Hogg-Dube syndrome Chromophobe and papillary clear cell RCC

MET Hereditary papillary renal cancer Type 1 papillary RCC

SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX

Hereditary pheochromocytoma and paraganglioma syndrome

Head and neck paragangliomas, thoracic/abdominal paragangliomas,

pheochromocytomasOther

PTCH1 Basal Cell Nevus Syndrome, GorlinSyndrome Skin BCCs

CDKN2A, BAP1, TERT, CDK4, CDK6 Hereditary melanoma Melanoma

NF1, NF2 Neurofibromatosis type1, 2 Brain, leukemia, benign tumors (1) Acoustic neuromas (2)

RB1 Retinoblastoma Retinoblastoma, sarcoma, melanoma

Summary of cancers associated with major autosomal dominantly inherited cancer predisposition syndromes

Gene(s) Syndrome Breast Ovarian Prostate Pancreatic Melanoma Colon Uterine Brain Kidney Stomach

BRCA1, BRCA2 HereditaryBreast/Ovarian

TP53 Li Fraumeni Syndrome

* Sarcoma

CDH1 Hereditary diffuse gastric cancer

PTEN Cowden Syndrome

STK11 Peutz JeghersSyndrome

* Non -epithelial

MLH1, MSH2, MSH6, PMS2

Lynch Syndrome

APC Familial Adenomatous

Polyposis (Gardner)

CDKN2A Melanoma-Astrocytoma or -

Pancreatic Syndrome

Summary of cancers associated with “newer” autosomal dominantly inherited cancer risk genes

Gene(s) Breast Ovarian Prostate Pancreatic Melanoma Colon Uterine Brain Kidney Stomach

ATM

BARD1

CHEK2

NBN

PALB2

BRIP1

RAD51C

RAD51D

Lynch:

Inherited (germline) mutations in a number of tumor suppressor genes may also lead to autosomal recessive inherited cancer susceptibility

Autosomal Recessive Cancer syndromes 101

Example of a typical Fanconi Anemia family

Autosomal recessive cancer syndromesGene(s) Syndrome Cancers

MUTYH MYH-associated polyposis Colorectal cancer

ATM* Ataxia telangiectasia Hematological malignancies

BLM Bloom Syndrome Hematological malignancies, gastric, colon, Skin SCCs

WAS Wiskott-Aldrich syndrome Hematological malignancies

NBN Nijmegen breakage syndrome Hematological malignancies,

medulloblastoma, glioma, rhabdomyosarcoma

FANCA, FANCB, FANCC*, BRCA2*, FANCD2, FANCE,

FANCF, XRCC9, FANCI, BRIP1*, FANCL, FANCM, PALB2*, RAD51C*, BRCA1*, REV7

Fanconi anemiaHematological malignancies,

SCCs (cervical, anal, HNSCCs, skin), medulloblastoma, Wilms tumor

TERT Dyskeratosis congenita Hematological malignancies, SCCs (cervical, anal, HNSCCs, skin)

SBDS Schwachman-Diamond syndrome Hematological malignancies,

MLH1*, MSH2*, MSH6*, PMS2*

Constitutional mismatch repair deficiency syndrome

Hematological malignancies, brain,embryonal tumors

DDB2, ERCC2, ERCC3, ERCC4, ERCC5 Xeroderma pigmentosum Skin SCCs, BCCs, and melanomas

WRN Werner syndrome Sarcoma, thyroid, melanoma

*Genes which also lead to increased cancer risk when monoallelic with autosomal dominant inheritance


Cancer risks



Cancer risks for BRCA1 and BRCA2 mutation carriers

http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

Cancer risks for Lynch Syndrome (MLH1, MSH2, MSH6, PMS2)

Cancer risks for expanded list of breast and ovarian cancer genesBLACK: BREASTBLUE: OVARIAN

Green: RR 1Orange: 2-fold (moderate)Red: 4-fold (high)

Relative Risk BREAST OVARIAN

HIGH(>4-fold)

BRCA1BRCA2

CDKN2APTENPALB2TP53

BRCA1BRCA2BRIP1

RAD51CRAD51D

MSH2MSH6TP53

MODERATE(2-4 fold)

CDH1ATM

BARD1

ATMPALB2NBN

LOW(1-2 fold)

BRIP1CHEK2MSH2MSH6

NO ASSOC

APC, BLM, FANCM,FANCC, NBN, NF1,MLH1, MRE11A,PMS2, RAD50,

RAD51C, RAD51D,XRCC2

BARD1, CHEK2,FANCC, FANCM,MLH1, MRE11A,

PMS2, PTEN, RAD50

No DataAPC, BLM, CDKN2A,CDH1, FANCC, NF1,

XRCC2

Suszynska et al Gyn Onc 2019

Cancer risks for expanded list of colon cancer genes


Medical Management for carriers



Summary of medical management of cancer risk

Management of Cancer

Risk


Risk

ScreeningScreening

PreventionPrevention

Targeted TreatmentTargeted

Treatment

Family PlanningFamily

Planning

Summary of medical management for BRCA1/2 Carriers


Risk


Risk

ScreeningScreening

PreventionPrevention


Treatment


Planning

• Enhanced breast screening (MRI/mammo)• Ovarian cancer screening (TVUS/CA125)• Pancreatic cancer screening (EUS or MRCP)• Prostate cancer screening (PSA/DRE)

• Tamoxifen or raloxifene (breast)• Oral contraceptives (ovary)• Bilateral mastectomy• Salpingo-oophorectomy• Salpingectomy w/delayed oophorectomy

• Prenatal genetic diagnosis• Partner carrier screening (BRCA2)

• Platinum chemotherapy and/or PARP inhibitors

Summary of medical management in Lynch syndrome


Risk


Risk

ScreeningScreening

Preventive Surgery

Preventive Surgery


Treatment


Planning

• Enhanced colonoscopy screening• Ovarian cancer screening (TVUS/CA125)• Endometrial sampling• Urinalysis

• Aspirin (colon)• Oral contraceptives (ovarian)• Total abdominal hysterectomy• Salpingo-oophorectomy

• Prenatal genetic diagnosis• Partner carrier screening

• Immune checkpoint blockade


Cancer genetic testing 2020



Adult cancer risk evaluation -2020

Many more genes with more options for ordering, including custom panel orders

Until 2013…

-> Take home: you cannot assume what genes have been evaluated unless you see the report

How your patient may find out they have a mutation Traditional Genetic Testing

• Meet with a cancer genetic counselor (GC) for pre-test counselling -> GC orders genetic testing -> meet with GC for post-test counselling -> meet with MD to come up with medical management plan

• May incorporate web-based or telegenetics

Point of Care testing• For cancer patients: Provider (ie oncologist) discusses genetic testing briefly (video, pamphlet) -> Provider

orders genetic testing -> meet with GC and Genetics MD only if positive result, VUS, confusing results, patient request

• Proposed for Ashkenazi Jewish individuals: population based screening, for example with gynecologist

Somatic testing -> germline testing• Mutation in a cancer risk gene found on tumor testing -> recommended followup

Research study enrollment (ie Geisinger biobank) -> incidental findings

Direct to consumer testing

Direct to Consumer Genetic Testing

Somatic Cancer Genetics

Treatment Implications


Types of somatic alterations

Biological Function:“Phenotype”

Single mutation testingSingle gene testingMulti-gene testing (NGS)DNA :“Genotype”

RNA:“Gene Expression”

Protein: “Protein Expression”

SNP arraysCytogeneticsFISH

RT-PCRMicroarray

ImmunohistochemistryImmunofluorescenceWestern blotELISA

Signature-type assay

Some examples of FDA approved targeted therapies based on somatic genetic testing in solid tumors – by alteration

Genetic alteration Cancer FDA Approved Targeted therapiesEGFR exon19 and exon 21 mutations

Lung afatinib (Gilotrif), gefitinib (Iressa), osimertinib (Tagrisso), erlotinib (Tarceva)

BRAF V600E, V600K mutations Melanoma Lung

V600E only - vemurafenib (Zelboraf)dabrafenib (Tafinlar), trametinib (Mekinist)

MET exon 14 skipping Lung capmatinib (Tabrecta)ALK rearrangements Lung crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa)

ERBB2 amplification Breast trastuzumab (Herceptin), ado-trastuzumab-emtansine(Kadcyla), pertuzumab (Perjeta)

PIK3CA mutations Breast alpelisib (Piqray)KRAS and NRAS wildtype (no mutations

Colorectal KRAS only - cetuximab (Erbitux)KRAS and NRAS – panitumumab (Vectibix)

FGFR2 rearrangementsFGFR2/FGFR3 mutations

CholangiocarcionomaBladder

pemigatinb (Pemazyre)erdafitinib (Balversa)

BRCA1/BRCA2, other DNA repair mutations

Ovarian, Prostate, Breast olaparib (Lynparza), rucaparib (Rubraca), veliparib (no brand), talozaparib (Talzenna)

Tumor agnostic approvals – a new territory for the FDA

Genetic alteration FDA Approved Targeted therapies

Tumor mutational burden highMicrosatellite instability highMismatch repair deficient

pembrolizumab (Keytruda)

NTRK gene fusion larotrectinib (Vitrakvi)entrectinib (Rozlytrek)

Somatic Cancer Genetics

Somatic Genetic Testing in 2020


Major Tumor Genetic testing platforms

Academic Platforms• Some Northeast examples:

– Memorial Sloan Kettering’s “IMPACT”– Penn Medicine “CPD”

Company Platforms• Foundation Medicine• Caris Life Sciences

Just to make it more confusing… enter Liquid Biopsy




Cell-free (cfDNA) is derived from:- Lymphocytes- Many disease states (ESRD, CVA, MI, surgery, trauma)- Fetal-derived- Non-human sources- Tumor-derived (ctDNA)

Proportion of ctDNA in cfDNA?- Huge range- Can be none or <1%- Maybe as high as 90%

Blood -> LymphocytesTumor

Both germline and liquid biopsy based testing can be confounded by CHIPCHIP (Clonal hematopoiesis of indeterminate potential)- acquired somatic mutations in

lymphocytes

- Frequency increases with age (~15% of >80yo)

- Leads to mutations in blood-based testing may be due to CHIP and not be inherited

- Associated with increased risk of cardiovascular disease and hematological malignancies

Germline variants (GV)Inherited from parents, found in egg and sperm

De novo Variants (DNV)Arise in the embryo OR de novo in the parents’ egg or sperm

Post-zygotic Variants (PZV)Arise during embryo development

CHIP Variants (CHIPV)Arise just in lymphocytes mostly during aging

Genetic Testing Results = GV + DNV + PZV + CHIPV

Summary of Cancer Genetic Testing - 2020

Germline Testing Tumor Testing Liquid Biopsy

Companies (examples)

Ambry, GeneDx, Invitae, Myriad Caris, Foundation Foundation

What is sequenced?

Blood lymphocytes (from whole blood or saliva)

Tumor (and sometimes matched blood)

Blood plasma (from whole blood)

What mutations can you get?

Germline (inherited)De novoPost-zygoticAcquired lymphocyte (CHIP)

All on germline testingPLUSTumor mutations(lab may subtract germline mutations)

All on germline testingPLUSTumor mutations IF the circulating tumor fraction is high enough

Online Resources

ASCO Meeting Library• https://meetinglibrary.asco.org/

ACMG Guidelines• Cancer Risk Referral guidelines:

https://www.acmg.net/docs/ACMG_Practice_Guideline_Referral_Indications_for_cancer_predisposition.pdf

NCCN guidelines • https://www.nccn.org/ - (Need free login) - Genetic/Familial High-Risk Assessment: Breast and

Ovarian , Genetic/Familial High-Risk Assessment: Colorectal , Prostate Cancer Early Detection

NCI (Cancer.gov)• https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-

sheet

genetics in cancer diagnosis and treatment

Documents