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Germline EGFR Mutations and Familial Lung Cancer

Publication: Journal of Clinical Oncology

Abstract

Purpose

The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs).

Methods

The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in person or remotely, providing germline testing and follow-up.

Results

A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.

Conclusion

To our knowledge, this is the first prospective description of familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR T790M variant enriched in the Southeast United States. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.

Introduction

Cancer genomics has transformed our understanding and treatment of non–small-cell lung cancer (NSCLC), yet in contrast, our understanding of the germline genetics associated with lung cancer risk has evolved relatively little. Somatic genotyping of genes such as EGFR, ALK, and ROS1, among others, is now routine in the care of advanced NSCLC because mutations in these genes can indicate sensitivity to oral targeted therapies.1 Such targetable mutations are detected more commonly in NSCLC occurring in patients with no history of cigarette smoking. Lung cancer in never smokers is increasingly recognized as a major health problem worldwide,2 and will persist even as the incidence of smoking-related lung cancers continues to decline. However, our understanding of lung cancer risk, particularly inherited risk, is inadequate to explain the widespread prevalence of lung cancer in never smokers.

Context

Key Objective
What is the lung cancer risk and clinical phenotype in individuals and families harboring an EGFR T790M pathogenic germline variant?
Knowledge Generated
More than half of germline carriers of EGFR T790M were diagnosed with lung cancer by age 60 years, and lung nodules were common in those without a cancer diagnosis. Lung cancers in germline carriers commonly carried a somatic driver EGFR mutation and had favorable outcomes on osimertinib. Genome-wide haplotyping identified a large and recent haplotype shared by most germline carriers.
Relevance (T.E. Stinchcombe)
This cohort study of participants and kindreds with germline an EGFR T790M pathogenic variant provides the data for future studies to better define the care of this patient population.*
*Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.
Although familial contributions to lung cancer risk have long been recognized, few high-risk germline variants have been identified.3 In 2005, Bell et al4 first described the germline EGFR T790M variant in a family of European descent with multiple members who developed lung adenocarcinoma. There have since been several case reports describing kindreds harboring this and other germline pathogenic variants (PVs) in EGFR (including R776H, V769M, and V834L).5-7 In 2012, we reported that the widespread use of somatic genotyping of NSCLC could offer an opportunity to identify patients with lung cancer at risk of carrying germline EGFR T790M PV. Because the somatic EGFR T790M mutation is usually detected only after acquired drug resistance to targeted therapy, its presence at initial diagnosis suggests the possibility of a germline allele.8
This study, Investigating HEreditary RIsk from T790M (INHERIT), was launched to prospectively evaluate the prevalence of germline EGFR T790M in patients harboring this variant on tumor genotyping at diagnosis, as well as to describe this rare hereditary syndrome. With the expectation that these families would be difficult to identify, the study offered remote enrollment, counseling, and testing to increase the referral base. The study was coordinated by the Addario Lung Cancer Medical Institute (ALCMI).9

Methods

The INHERIT study (ClinicalTrials.gov identifier: NCT01754025) was a prospective diagnostic study with institutional review board approval at three ALCMI sites (Dana-Farber Cancer Institute, Vanderbilt-Ingram Cancer Center, and James Cancer Center at the Ohio State University). Participants were eligible if (1) they had a cancer diagnosis with tumor genotyping positive for EGFR T790M (pretreatment) or another EGFR mutation previously described as a germline PV (eg, R776H), or if (2) a relative or (3) they themselves had previous germline testing positive for a PV in EGFR (Fig 1). The study was amended in 2015 to also allow enrollment based upon high levels of EGFR T790M (>40% variant allele frequency, VAF) detected on genotyping of plasma DNA.10 Eligibility was limited to those age 18 years or older and able to complete the study procedures. Originally, the study was limited to those able to speak and read English but was later amended to allow enrollment of a Portuguese-speaking patient from Brazil. Participants could enroll locally at a participating site or remotely through an online referral system.11 All participants provided consent in person or by phone.
Fig 1. Schema of INHERIT EGFR study. Participants were eligible based on previous cancer genotyping results (positive for EGFR T790M [pretreatment] or another EGFR mutation previously described as a pathogenic germline variant [eg, R776H]), or if they or a relative were a known germline carrier. Eligible participants were enrolled and offered germline testing after genetic counseling and were followed for 2 years. Those found to be germline-positive could invite their relatives to be considered for study enrollment. Participation could be remote or in person at a study site. CT, computed tomography; INHERIT, Investigating HEreditary RIsk from T790M.
After consent, participants submitted saliva or blood for Sanger sequencing of the EGFR kinase domain performed at the Laboratory for Molecular Medicine of Partners HealthCare. Testing was performed under Clinical Laboratory Improvement Amendments conditions and a report was provided to the study team. Positive results from saliva were recommended to be confirmed by blood. Results were confidential and not entered into the medical record unless participants independently notified their medical providers. The primary objective was to understand the prevalence of germline EGFR PVs in patients with eligible EGFR mutations detected on their tumor profiling.
For participants interested in learning genetic testing results, genetic counseling was provided by a study genetic counselor in person or by phone (Fig 1). Participants spoke with the genetic counselor regarding potential implications and limitations, and a three-generation family history was obtained. When test results were available, participants were notified by mail to call their genetic counselor to learn the results. For participants with positive test results, a genetic counselor reviewed the pedigrees and identified eligible relatives who could be invited to participate in the study; study packets were then sent to the participant to mail to invited relatives, if desired. Participants not interested in receiving germline testing results could provide consent and a specimen for research without receiving their results or genetic counseling.
Participants completed a survey at enrollment to provide baseline demographic information. For those with a cancer diagnosis, paraffin-embedded tumor specimens were collected for pathologic review and next-generation sequencing (NGS) using an institutional 282-gene OncoPanel described previously, with genomic features then compared with an institutional cohort.12 Computed tomography (CT) imaging was not required for unaffected germline carriers but was recommended. Chest CT scans were collected when available, and were retrospectively reviewed (M.M.S., Columbia University) to assess for nodules per LungRADS criteria.13 All participants were followed for 2 years after date of consent, regardless of test results.
As an exploratory analysis, germline DNA was submitted for genome-wide genotyping on the Illumina OmniExpress high-density SNP array for patients with specimens available. Shared genomic segment analysis (SGS, performed by C.C.T. and A.T.) was used to identify runs of successive genetic markers in genotyped individuals that were indicative of a shared haplotype.14 Long runs of consistently shared successive markers (>3 cM) are indicative of possible identity-by-descent inheritance from a common ancestor.15 SGS was used to estimate the lengths of shared haplotypes surrounding the T790M locus among the 46 T790M carriers. The length of the shared segment, L, among a subset of carriers, k, was used to estimate the number of meioses, d, separating the k individuals, assuming 1 cM is equivalent to 1 Mb. Assuming dL/100 is a Γ(2,1) random variable provides a point estimate and 95% CI for d.16 The number of generations between k haplotype carriers and a common ancestor (time-to-coalescence) could then be estimated.17

Results

A total of 141 participants were enrolled to the study between December 2012 and April 2018 (Table 1). Participants were from 62 apparently unrelated kindreds. Participants were largely from the United States (n = 138; 33 different states), although included enrollment from Australia (n = 2) and Brazil (n = 1). Initially, enrollment was greater from participating sites; however, as the study proceeded and awareness increased, remote enrollment accelerated (Appendix Fig A1, online only). A total of 351 individuals reached out via the online mechanism, of whom 39 consented and enrolled; the majority of these reported they were referred by their physician, but six reached out to the study team independently. Most individuals screened remotely were ineligible, either having a family history of lung cancer without an EGFR mutation of interest or having lung cancer harboring an acquired EGFR T790M resistance mutation. One participant enrolled into the study without knowing a cousin had already enrolled.
Table 1. Characteristics of the Study Population
All 141 participants agreed to learn germline testing results at time of enrollment, and testing was completed on 131; of the 10 not tested on study, most either did not complete the counseling or did not submit a specimen. Based upon their previous somatic or germline genotyping, 116 participants from 59 kindreds were tested for germline EGFR T790M, 14 participants from one kindred were tested for germline EGFR R776H, and one participant was tested for germline EGFR G724S (Table 1). Results were returned for 121 participants: six did not return calls or letters offering return of results and four died before results were available and did not provide a relative for contact.
Among 100 participants tested for EGFR T790M (omitting 16 known germline T790M carriers at time of enrollment), germline prevalence was consistent with Mendelian inheritance. Of 46 with lung cancer harboring somatic EGFR T790M at diagnosis, 24 (52%) were positive for a germline PV. Another 37 participants were first-degree relatives of germline carriers, and 20 (54%) were positive; five of 16 (31%) second-degree relatives of germline carriers were positive; one third-degree relative tested negative (Appendix Table A1).
A total of 76 participants carrying a germline EGFR PV were enrolled from 39 different kindreds, with family history available for 37 (one did not provide, one was adopted). Within the 39 kindreds, 91 confirmed or obligate germline EGFR PV carriers were identified. Of the carriers, 41 (45%) were unaffected with lung cancer ranging in age from 29 to 83 years (median age, 47 years) and 50 (55%) were affected with lung cancer ranging in age at diagnosis from 28 to 83 years (median age, 56 years). Among the carriers, 2/89 (2.2%) were diagnosed with lung cancer by age 30 years, 7/76 (9.2%) by age 40 years, 15/70 (21%) by age 50 years, and 34/65 (52%) were diagnosed by age 60 years.
Family history of lung cancer was common in carriers of germline EGFR PV; however, penetrance was variable both within and among kindreds. For the purposes of this study, proband was defined as the first member of a kindred who was found to carry a germline EGFR PV; all probands were affected with lung cancer. In two kindreds, the proband was not enrolled in the study, but their history was reported by an enrolled family member. Of 37 probands with family history collected, 13 (35%) reported a first-degree relative with a history of lung cancer and 10 (27%) reported more than one first-degree relative. Some families had strikingly high penetrance, with multiple first-degree relatives affected with lung cancer, regardless of smoking status (Fig 2A, Appendix Fig A2A). Other families showed more variable penetrance, such as a proband with lung cancer at age 46 years whose brother developed lung cancer at age 21 years (before EGFR testing was available), while his 55-year-old sister and 82-year-old father carry the EGFR PV, yet have never been diagnosed with lung cancer (Fig 2B), and few families showed only an isolated case of lung cancer (Appendix Fig A2B). Penetrance was high in the one family carrying germline EGFR R776H (Appendix Fig A2C). Pedigree analysis used the standard pedigree nomenclature guideline endorsed by National Society of Genetic Counselors.18
Fig 2. Pedigrees of affected families exhibit variable penetrance across generations. Current age or age at death/diagnosis are provided, as well as those who tested positive (+), negative (−), or obligate carriers (*). (A) Lung cancer can occur with or without smoking history, and (B) although it can be diagnosed early in life, some carriers remain without lung cancer late in life. BR, breast cancer; CATYPE, cancer (type unknown); CO, colon cancer; LG, lung cancer; LK, leukemia; PR, prostate cancer.
We further studied the 42 participants with lung cancer in the setting of an underlying germline EGFR PV (Table 1), involving 38 apparently unrelated kindreds. Median age at lung cancer diagnosis was 57 years (range, 27-82). More than half were never smokers (25; 60%), and the majority had stage IV disease at diagnosis (22; 52%). Adenocarcinoma was the most prevalent subtype of NSCLC (38; 91%), followed by NSCLC not otherwise specified (4; 9.5%). Most subjects self-identified as White (36; 86%) and the remaining as Black (6; 14%). Of 38 germline T790M-positive lung cancer participants, the majority (22; 58%) were from the US South; this distribution differed from the geographic distribution of 22 participants with somatic-only T790M-positive lung cancer, of whom six were from the US South (27%; P = .032; Fig 3).
Fig 3. Enrichment of germline carriers in the Southeast United States. (A) Although the majority of probands (index carriers from involved kindreds) were enrolled from the Southeast or bordering states, (B) participants with lung cancer but without germline mutations were enrolled from across the United States.
To better understand this apparent geographic enrichment, we performed genome-wide germline haplotyping of 46 participants carrying germline T790M (with and without lung cancer) from 30 kindreds to test for a founder effect. SGS analysis of the 46 participants genotyped on the high-density SNP platform identified a cluster of 41 distantly related individuals with clear evidence of a long-shared haplotype spanning 51.6-55.7 Mb surrounding the T790M mutation (Appendix Fig A3), as well as an additional individual who shared a smaller segment of that haplotype. The remaining four participants included one individual who did not share a long segment with anyone else, who may be a de novo germline carrier, and a nuclear family trio with a distinct haplotype. For the 41 subjects sharing the 4.1-Mb haplotype, the estimated number of generations to a common ancestor is 11.2 (95% CI, 1.4 to 31.1), suggesting a shared ancestor approximately 223-279 years before.
Of the 42 participants with lung cancer and a germline PV, 37 had somatic EGFR genotyping, and an EGFR comutation was detected in 35 (95%). Compared with an institutional cohort of 364 lung cancer cases with somatic mutations in the EGFR kinase domain, the spectrum of the 36 somatic EGFR mutations seen in 35 germline carriers was atypical (Appendix Fig A4). Although EGFR L858R was common in both cohorts (42% of germline cases, 29% of institutional cohort), exon 19 deletions are usually common (30% of institutional cohort) but were found in only 17% of germline cases, while 14 germline cases (39%) harbored EGFR point mutations (G719X, H773R, V774M, and L861X) found rarely in the institutional cohort (9%; P < .001). Among 19 lung cancers with tumor NGS available, and excluding the known germline PV, EGFR was the most commonly mutated gene (89%), followed by TP53 (47%; Appendix Fig A5); median tumor mutational burden was 7.3 mutations/mb. The two cancers with germline T790M without a somatic EGFR comutation were both in patients with a smoking history; these two alone had evidence of a smoking signature on their tumor NGS.19
Among 38 patients with lung cancer and germline EGFR T790M, survival from date of diagnosis was estimated at a median of 47 months, and median survival for 22 patients with advanced disease was 36 months (Fig 4). Fourteen of these patients received treatment with a next-generation EGFR inhibitor, osimertinib, with potent activity against EGFR T790M,20 with durable effect seen in the majority of patients (Fig 4). The first patient on study treated with osimertinib developed extreme fatigue weeks after starting therapy, raising concern for drug toxicity, but this resolved with steroids and was attributed to recent brain radiation. This patient was able to receive osimertinib at a reduced dose for over 5 years. No other unexpected toxicity was identified among the other patients carrying germline EGFR T790M treated with osimertinib.
Fig 4. Lung cancer outcomes in germline carriers. Kaplan-Meier curves showing (A) survival from date of diagnosis for 22 patients with germline T790M and stage IV lung cancer and (B) survival from date of diagnosis for 38 patients with germline T790M regardless of lung cancer stage. (C) In germline carriers receiving osimertinib, duration of therapy was prolonged without unexpected toxicity.
Phenotype was studied in 36 unaffected relatives with germline EGFR PVs who underwent CT scans under the care of their local physician. Among 15 patients with CT scans available, abnormal CT findings were common, with nine participants having evidence of lung nodules, including one patient with >10 lung nodules at age 28 years (Fig 5). Additionally, one of these individuals went on to develop lung cancer during the follow-up period, as described previously.21 Among 41 individuals with germline EGFR mutations and a diagnosis of lung cancer at enrollment, retrospective imaging was available for one patient extending back 9 years before diagnosis and showed lung nodules growing slowly over this extended period (Fig 5).
Fig 5. Lung nodules in germline carriers. (A) Bilateral asymptomatic lung nodules in a germline carrier presenting in their early 30s with no smoking history. (B) In a 77-year-old patient who went on to develop lung cancer, evolution into multifocal malignancy was observed over the course of 9 years.

Discussion

In this prospective cohort study, we report on 77 individuals from 39 kindreds carrying pathogenic germline variants in EGFR. Although previous reports of germline EGFR PVs have been largely limited to individual select kindreds, to our knowledge, this is the first prospective study of multiple unrelated kindreds with pathogenic germline variants in EGFR, allowing us to better understand the characteristics of these patients and their families. Our data confirm the existence of an underappreciated syndrome of familial EGFR-mutant lung cancer predisposition. Familial EGFR-mutant lung cancer syndrome is characterized by (1) development of lung adenocarcinomas harboring an atypical spectrum of somatic EGFR mutations and (2) high prevalence of lung nodules in germline carriers without a lung cancer diagnosis. We find that in individuals with familial EGFR-mutant lung cancer, lung nodules can be found as early as the third decade of life and can be stable for many years, potentially consistent with adenocarcinoma in situ.
This syndrome is one of few inherited cancer syndromes in which the pathogenic germline variant is in an oncogene (not a tumor suppressor gene). In this syndrome, nearly all lung neoplasms then develop a second hit somatic comutation identified in the same oncogene. This would suggest that mutations such as EGFR T790M and R776H may not be oncogenic on their own but require a second oncogenic mutation to lead to cancer neogenesis. We hypothesize that some of these patients may in fact have a multifocal, polyclonal process rather than a single metastatic neoplasm, as evidenced by the multiple nodules seen before cancer diagnosis (Fig 5) as well as the distinct somatic EGFR driver mutations, which can be seen at different disease sites in the same individual, as found by our group and others.22,23 Additionally, these patients can benefit durably from next-generation EGFR inhibitors such as osimertinib without any excess toxicity, despite osimertinib specifically targeting the T790M mutation.24 Given that next-generation EGFR inhibitors are safe in these patients and have a relatively modest toxicity profile, these agents deserve study in the future not only as adjuvant therapy but potentially as a cancer interception strategy for patients with germline T790M and growing lung nodules.25
The most completely described germline EGFR PV, T790M, has been described largely in cases within the United States. Our study identified an unexpected enrichment within the US South, which we find may be due to a founder variant associated with a relatively recent North American haplotype. We acknowledge that our study was focused on enrolling English-speaking patients to facilitate remote genetic counseling and germline testing, which thus favored North American enrollment. Yet, a recent review of the testing experience by a commercial laboratory revealed 29 carriers of germline EGFR T790M with a racial distribution similar to our experience, among whom there were African American carriers, but no Asian, Hispanic, or Ashkenazi Jewish individuals testing positive for the PV (about 3,000 per group).26 Although our data suggest that de novo germline EGFR T790M can occur, the preponderance of available data suggests this germline variant may primarily exist within White/Black populations in North America. We hope that laboratories offering genome-wide germline screening may be able to use this haplotype (Appendix Fig A3) to identify individuals and families at risk of carrying EGFR T790M.
Although this study illustrates the risk of lung cancer in individuals with germline EGFR PVs, the optimal management of such families is not yet established; however, we can propose several management principles on the basis of our data. First, the identification of certain EGFR mutations at diagnosis (eg, T790M, R776H) on cancer genomic profiling, with or without a second EGFR driver mutation, should lead to the consideration of germline EGFR testing, particularly with an elevated VAF consistent with a possible germline variant.27 Patients with germline EGFR PVs may have multiple primary lung adenocarcinomas and may benefit from a personalized approach including local management of a dominant primary. For those with high risk or advanced cancers, we recommend osimertinib therapy that can be tolerated with durable effect.
Carriers of germline EGFR variants will need more precise estimates of penetrance to plan their care. Optimal surveillance for lung cancer has not been defined for carriers of pathogenic germline EGFR variants. Their risk of lung nodules is high, as is their risk of developing EGFR-mutant lung cancer. There have not yet been definitive estimates of the penetrance of germline EGFR pathogenic/likely PVs. We favor an initial low-dose screening CT in adult carriers to document lung nodules, with monitoring scans as appropriate if nodules are detected. In individuals with a negative screening CT scan, it is difficult to identify the optimal window for repeat CT imaging at this time, although the risk of nodules appears to increase with age. Further study of CT screening in this population is needed to enable more detailed consensus guidelines on management of this unique population. The opportunity to study EGFR-targeting agents such as osimertinib for cancer interception (risk reduction) in this population should also be examined.
This study of a rare patient population would not have been possible without mechanisms to support remote participation, including phone consent, phone counseling, and specimen collection by mail. Although these methods were novel when the study was initiated in 2012, they have grown increasingly common in recent years to enable study of rare cancer populations.28,29 Correlative and diagnostic research has grown increasingly challenging throughout the COVID-19 pandemic, highlighting the importance of patient-centered research methods such as remote participation to enable ongoing study of rare cancer syndromes. Even remote-participation approaches could risk capturing a biased population and must be paired with systematic efforts to refer appropriate patients for testing and enrollment. Efforts are currently underway to expand upon the data gathered from this study and subject population, including correlative studies with remote participation to examine the natural history and clinical characteristics of EGFR germline risk variants (T790M and others), which could lead to implementation of a screening component in patients identified to carry EGFR germline variants that increase risk of developing lung cancer.

Study Protocol

The following protocol information is provided solely to describe how the authors conducted the research underlying this article. The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors, JCO requests only specific elements of the most recent version of the protocol. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of this protocol material or due to any errors or omissions. Readers seeking additional information about the protocol are encouraged to consult the corresponding author directly.

Please click the protocol link below to access the information.

Prior Presentation

Presented in part at the 2015 ASCO Annual Meeting, Chicago, IL, May 29-June 2, 2015.

Support

Supported in part by the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, the Team Mitch Fund of the Dana-Farber Cancer Institute, Research Incentive Fund of Hospital de Clinicas de Porto Alegre (FIPE Grant no. 2018-0099), the Ingram Cancer Professorship at Vanderbilt Ingram Cancer Center, and the National Cancer Institute of the NIH (R01-CA114465).

Authors' Disclosures of Potential Conflicts of Interest

Germline EGFR Mutations and Familial Lung Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Geoffrey R. Oxnard

Employment: Foundation Medicine
Stock and Other Ownership Interests: Roche

Suzanne E. Dahlberg

Stock and Other Ownership Interests: United Health Group
Research Funding: Takeda (Inst)
Patents, Royalties, Other Intellectual Property: Methods of assessing tumor growth (Inst)

Irene Rainville

Employment: Myriad Genetics
Stock and Other Ownership Interests: Myriad Genetics

Kelly A. Taylor

Consulting or Advisory Role: Natera

Alicia Sable-Hunt

Consulting or Advisory Role: Fujirebio Diagnostics
Travel, Accommodations, Expenses: Fujirebio Diagnostics

Lynette M. Sholl

Stock and Other Ownership Interests: Moderna Therapeutics
Consulting or Advisory Role: Genentech (Inst), Lilly (Inst), AstraZeneca
Research Funding: Roche/Genentech (Inst), Bristol Myers Squibb (Inst)

André P. Fay

Honoraria: Pfizer, Novartis, Bristol Myers Squibb, AstraZeneca, Roche, Ipsen, Janssen Oncology, MSD
Consulting or Advisory Role: Novartis, Roche, Pfizer, Merck Sharp & Dohme, AstraZeneca, Ipsen

Patrícia Ashton-Prolla

Employment: Grupo Oncoclinicas
Research Funding: AstraZeneca (Inst)

Mary M. Salvatore

Consulting or Advisory Role: Boehringer Ingelheim
Speakers' Bureau: France Foundation, Peer View
Research Funding: Boehringer Ingelheim (Inst), Genentech (Inst)
Travel, Accommodations, Expenses: Peer View

Pasi A. Jänne

Stock and Other Ownership Interests: Gatekeeper Pharmaceuticals, Loxo
Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech, Duality Biologics
Research Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Daiichi Sankyo (Inst), Lilly (Inst), Boehringer Ingelheim (Inst), Puma Biotechnology (Inst), Takeda (Inst), Revolution Medicines (Inst)
Patents, Royalties, Other Intellectual Property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp I receive post-marketing royalties from this invention

David P. Carbone

Employment: James Cancer Center
Honoraria: AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical
Consulting or Advisory Role: Merck, AstraZeneca, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Genentech/Roche, Intellisphere, Lilly, Mirati Therapeutics, Johnson & Johnson/Janssen, Sanofi, AbbVie, Regeneron, PPD, Curio Science, Iovance Biotherapeutics, Jazz Pharmaceuticals, Merck KGaA, Novartis, Roche, InThought, OncLive/MJH Life Sciences, Pfizer, Arcus Biosciences, NCCN/AstraZeneca, MSD Oncology, JNJ, Roche/Genentech, BMS Israel, Genentech, Novocure, Oncohost

Georgia L. Wiesner

Employment: Vanderbilt University Medical Center

Judy E. Garber

Consulting or Advisory Role: Novartis, Kronos Bio, GV20 Therapeutics, Belharra Therapeutics, Inc, Earli, Inc
Research Funding: Novartis, Ambry Genetics, InVitae, Amgen
Other Relationship: AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrienne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered
No other potential conflicts of interest were reported.

Appendix

Fig A1. Cumulative enrollment over the study period. Although local enrollment at participating sites plateaued, remoted enrollment using the online referral system increased with time.
Image (JCO.23.01372app2-1) is missing or otherwise invalid.Image (JCO.23.01372app2-2) is missing or otherwise invalid.
Fig A2. Pedigrees of affected families exhibit reduced penetrance across generations. Additional pedigrees (A) from a family diagnosed with concurrent Lynch syndrome and (B) from a family with minimal lung cancer seen across a multigenerational pedigree. (C) Pedigrees of affected families exhibit variable penetrance across generations. Additional pedigree from a family carrying EGFR R776H. BR, breast cancer; CATYPE, cancer (type unknown); CO, colon cancer; LG, lung cancer; LK, leukemia; LV, liver cancer; MEL, melanoma; OV, ovarian cancer; PR, prostate cancer; RECT, rectal cancer; STO, stomach cancer; THR, throat cancer; UNP, cancer of unknown primary; UT, uterine cancer.
Fig A3. Shared haplotype. Genome-wide haplotyping of 46 participants with germline EGFR T790M identified 41 distantly related individuals with clear evidence of a long-shared haplotype surrounding the T790M mutation spanning 51.6-55.7 Mb.
Fig A4. Spectrum of somatic EGFR mutations. (A) The 36 somatic EGFR mutations detected in germline carriers were enriched for L858R and rarer point mutations, (B) with relatively fewer exon 19 deletions than were detected in an institutional cohort of EGFR kinase domain mutations used as a comparison.
Fig A5. Lung cancer genomics in germline carriers. Among 19 patients with tumor NGS available, and excluding the known germline EGFR mutation, EGFR was the most commonly mutated gene followed by TP53. The two cancers harboring a germline T790M mutation without a somatic EGFR comutation were both patients with a heavy smoking history; these two alone had evidence of a smoking signature on their tumor NGS. NGS, next-generation sequencing.
Table A1. Table Further Stratifying the Numbers of Each of the Different Cohorts

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Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 5274 - 5284
PubMed: 37579253

History

Published online: October 23, 2023
Published in print: December 01, 2023

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Authors

Affiliations

Dana-Farber Cancer Institute, Boston, MA
Dana-Farber Cancer Institute, Boston, MA
Jennifer C. Pharr, MD
Dana-Farber Cancer Institute, Boston, MA
Diane R. Koeller, MS, MPH, CGC https://orcid.org/0000-0003-1217-9514
Dana-Farber Cancer Institute, Boston, MA
Dana-Farber Cancer Institute, Boston, MA
Suzanne E. Dahlberg, PhD https://orcid.org/0000-0001-5139-831X
Dana-Farber Cancer Institute, Boston, MA
Irene Rainville, PhD, CGC https://orcid.org/0000-0001-5865-3467
Dana-Farber Cancer Institute, Boston, MA
Ohio State University Medical Center, Columbus, OH
Kelly A. Taylor, MS, LCGC, CCRIP
Vanderbilt-Ingram Cancer Center, Nashville, TN
Alicia Sable-Hunt, RN, MBA, CCRA, ACRP-PM
Addario Lung Cancer Medical Institute (ALCMI), San Carlos, CA
Brigham and Women's Hospital, Boston, MA
Craig C. Teerlink, PhD
Huntsman Cancer Center, Salt Lake City, UT
Alun Thomas, PhD
Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT
Lisa A. Cannon-Albright, PhD https://orcid.org/0000-0003-2602-3668
Huntsman Cancer Center, Salt Lake City, UT
André P. Fay, MD
PUCRS School of Medicine, Porto Alegre, Brazil
Patrícia Ashton-Prolla, MD, PhD https://orcid.org/0000-0002-5093-4739
PUCRS School of Medicine, Porto Alegre, Brazil
Hao Yang, MS
Columbia University Medical Center, New York, NY
Mary M. Salvatore, MD
Columbia University Medical Center, New York, NY
Bonnie J. Addario
Addario Lung Cancer Medical Institute (ALCMI), San Carlos, CA
Dana-Farber Cancer Institute, Boston, MA
David P. Carbone, MD, PhD https://orcid.org/0000-0003-3002-1921
Ohio State University Medical Center, Columbus, OH
Georgia L. Wiesner, MD, MS https://orcid.org/0000-0001-8897-7008
Vanderbilt-Ingram Cancer Center, Nashville, TN
Dana-Farber Cancer Institute, Boston, MA

Notes

Geoffrey R. Oxnard, MD, Boston Medical Center, 830 Harrison Ave, Boston, MA 02118; e-mail: [email protected].

Author Contributions

Conception and design: Geoffrey R. Oxnard, Suzanne E. Dahlberg, Bonnie J. Addario, Pasi A. Jänne, David P. Carbone, Georgia L. Wiesner, Judy E. Garber
Financial support: Geoffrey R. Oxnard, Pasi A. Jänne, Georgia L. Wiesner, Judy E. Garber
Administrative support: Alicia Sable-Hunt, Judy E. Garber
Provision of study materials or patients: Kate Shane-Carson, Kelly A. Taylor, Alicia Sable-Hunt, Lisa A. Cannon-Albright, André P. Fay, Patrícia Ashton-Prolla, Bonnie J. Addario, Pasi A. Jänne, Georgia L. Wiesner
Collection and assembly of data: Ruthia Chen, Jennifer C. Pharr, Diane R. Koeller, Arrien A. Bertram, Irene Rainville, Kate Shane-Carson, Kelly A. Taylor, Alicia Sable-Hunt, Craig C. Teerlink, Lisa A. Cannon-Albright, André P. Fay, Patrícia Ashton-Prolla, Mary M. Salvatore, Bonnie J. Addario, Georgia L. Wiesner, Judy E. Garber
Data analysis and interpretation: Ruthia Chen, Diane R. Koeller, Arrien A. Bertram, Suzanne E. Dahlberg, Lynette M. Sholl, Craig C. Teerlink, Alun Thomas, Lisa A. Cannon-Albright, Patrícia Ashton-Prolla, Hao Yang, Mary M. Salvatore, Bonnie J. Addario, Pasi A. Jänne, Georgia L. Wiesner, Judy E. Garber
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Disclosures

Geoffrey R. Oxnard
Employment: Foundation Medicine
Stock and Other Ownership Interests: Roche
Suzanne E. Dahlberg
Stock and Other Ownership Interests: United Health Group
Research Funding: Takeda (Inst)
Patents, Royalties, Other Intellectual Property: Methods of assessing tumor growth (Inst)
Irene Rainville
Employment: Myriad Genetics
Stock and Other Ownership Interests: Myriad Genetics
Kelly A. Taylor
Consulting or Advisory Role: Natera
Alicia Sable-Hunt
Consulting or Advisory Role: Fujirebio Diagnostics
Travel, Accommodations, Expenses: Fujirebio Diagnostics
Lynette M. Sholl
Stock and Other Ownership Interests: Moderna Therapeutics
Consulting or Advisory Role: Genentech (Inst), Lilly (Inst), AstraZeneca
Research Funding: Roche/Genentech (Inst), Bristol Myers Squibb (Inst)
André P. Fay
Honoraria: Pfizer, Novartis, Bristol Myers Squibb, AstraZeneca, Roche, Ipsen, Janssen Oncology, MSD
Consulting or Advisory Role: Novartis, Roche, Pfizer, Merck Sharp & Dohme, AstraZeneca, Ipsen
Patrícia Ashton-Prolla
Employment: Grupo Oncoclinicas
Research Funding: AstraZeneca (Inst)
Mary M. Salvatore
Consulting or Advisory Role: Boehringer Ingelheim
Speakers' Bureau: France Foundation, Peer View
Research Funding: Boehringer Ingelheim (Inst), Genentech (Inst)
Travel, Accommodations, Expenses: Peer View
Pasi A. Jänne
Stock and Other Ownership Interests: Gatekeeper Pharmaceuticals, Loxo
Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech, Duality Biologics
Research Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Daiichi Sankyo (Inst), Lilly (Inst), Boehringer Ingelheim (Inst), Puma Biotechnology (Inst), Takeda (Inst), Revolution Medicines (Inst)
Patents, Royalties, Other Intellectual Property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp I receive post-marketing royalties from this invention
David P. Carbone
Employment: James Cancer Center
Honoraria: AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical
Consulting or Advisory Role: Merck, AstraZeneca, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Genentech/Roche, Intellisphere, Lilly, Mirati Therapeutics, Johnson & Johnson/Janssen, Sanofi, AbbVie, Regeneron, PPD, Curio Science, Iovance Biotherapeutics, Jazz Pharmaceuticals, Merck KGaA, Novartis, Roche, InThought, OncLive/MJH Life Sciences, Pfizer, Arcus Biosciences, NCCN/AstraZeneca, MSD Oncology, JNJ, Roche/Genentech, BMS Israel, Genentech, Novocure, Oncohost
Georgia L. Wiesner
Employment: Vanderbilt University Medical Center
Judy E. Garber
Consulting or Advisory Role: Novartis, Kronos Bio, GV20 Therapeutics, Belharra Therapeutics, Inc, Earli, Inc
Research Funding: Novartis, Ambry Genetics, InVitae, Amgen
Other Relationship: AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrienne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered
No other potential conflicts of interest were reported.

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Geoffrey R. Oxnard, Ruthia Chen, Jennifer C. Pharr, Diane R. Koeller, Arrien A. Bertram, Suzanne E. Dahlberg, Irene Rainville, Kate Shane-Carson, Kelly A. Taylor, Alicia Sable-Hunt, Lynette M. Sholl, Craig C. Teerlink, Alun Thomas, Lisa A. Cannon-Albright, André P. Fay, Patrícia Ashton-Prolla, Hao Yang, Mary M. Salvatore, Bonnie J. Addario, Pasi A. Jänne, David P. Carbone, Georgia L. Wiesner, Judy E. Garber
Journal of Clinical Oncology 2023 41:34, 5274-5284

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