Germline genetic testing is transforming cancer treatment by guiding therapy selection, uncovering inherited cancer risk, and identifying patients who benefit from targeted therapies. In this keynote from the Precision Oncology Summit, Dr. Stephen B. Gruber explores real-world cases and INSPIRE study data that reveal why current testing guidelines miss most mutation carriers—and why universal access to comprehensive germline testing represents the future of precision oncology.

An internationally recognized cancer geneticist and oncologist, Stephen Gruber, M.D., Ph.D., M.P.H., is a physician-scientist who focuses his clinical practice and research program on precision medicine and the genomics of cancer in order to improve treatment and care for cancer patients and their families. Dr. Gruber is an expert in Lynch syndrome and hereditary susceptibility to colorectal cancer, and he has broad experience in the care of patients and families with inherited susceptibility to cancer. He leads the Center for Precision Medicine at City of Hope.

This video features a keynote lecture at the Precision Oncology Summit, where Dr. Gruber explores how germline testing influences therapy selection and patient outcomes, while examining the limitations of current consensus guidelines.

The transcript below has not been reviewed by the speaker and may contain errors.

Introduction to Germline Testing and Precision Oncology in Cancer Care

Germline genetic testing has emerged as a critical component of modern cancer treatment, extending far beyond its traditional role in identifying hereditary cancer risk. The discussion highlights findings from the INSPIRE study at City of Hope, which demonstrates significant gaps in guideline-based testing approaches and makes a compelling case for universal access to germline genetic testing.

Three primary goals frame this discussion: first, recognizing indications for germline genetic testing based on consensus guidelines; second, appreciating the clinical utility of germline testing for therapy selection in specific cancer genetic syndromes; and third, understanding how consensus guidelines continue to evolve with the introduction of universal access to germline genetic testing.

Case Study: BRIP1 Mutation and Ovarian Cancer Treatment Decisions

A 59-year-old woman presented with a history of chronic lymphocytic leukemia (CLL) diagnosed at age 51, which had entered remission after extensive therapy. An October scan revealed suspicious abdominal findings, initially thought to be recurrent lymphadenopathy. Her family history included breast cancer in her mother at age 72 and ovarian cancer in her grandmother at 76.

Her mother had previously undergone genetic testing with a small panel including BRCA1 and BRCA2, testing negative for both genes and reassuring her children they had no inherited cancer susceptibility. However, when the patient's abdominal mass was confirmed as FIGO stage 3C high-grade serous ovarian carcinoma, comprehensive genetic testing revealed a BRIP1 pathogenic variant.

BRIP1 (BRCA1 Interacting Protein 1) is a Fanconi anemia gene required for chromosomal stability maintenance. It functions late in the Fanconi anemia pathway and participates in DNA double-strand break repair through homologous recombination in a manner dependent on its interaction with BRCA1. Carriers of BRIP1 pathogenic variants face a lifetime ovarian cancer risk of approximately 15%.

Initially, the patient declined treatment, devastated by her diagnosis and exhausted from her previous CLL therapy. She was particularly distressed knowing she had chosen not to have children and could have undergone preventive oophorectomy years earlier if the mutation had been identified. However, learning that BRIP1 mutations confer platinum sensitivity and likely homologous recombination deficiency (HRD) positive status completely changed her perspective on treatment.

Based on the PALO1 trial, which demonstrated that platinum-based first-line therapy combined with olaparib and bevacizumab significantly enhances cure potential in HRD-positive tumors, the patient reversed her decision. The trial's five-year updated progression-free survival data showed substantially higher proportions of patients without relapse on olaparib plus bevacizumab (hazard ratio 0.41, five-year progression-free survival 46% versus 19%).

Following maximal debulking surgery in April and carboplatin-paclitaxel therapy starting March 8th, the patient achieved complete remission. Additionally, genetic testing of her two sisters revealed one carried the same BRIP1 mutation and subsequently underwent risk-reducing salpingectomy and oophorectomy with normal CA125 and CA19-9 levels, preventing a potential future cancer.

Evolution of Precision Medicine and FDA-Approved Germline Testing Applications

Precision oncology and precision medicine have advanced dramatically since the 2015 New England Journal of Medicine paper by Francis Collins and Harold Varmus, which coincided with a presidential State of the Union address committing to transforming healthcare through precision medicine. Substantial progress has occurred over the past decade.

Multiple FDA companion diagnostics for targeted therapies are now driven by germline testing. Key germline-associated markers include microsatellite instability, tumor mutational burden, PALB2, BRIP1, BRCA1 and BRCA2, ATM, CHEK2, and mismatch repair genes. Additional germline mutations with therapeutic implications continue to emerge, requiring ongoing education through conferences and literature review to maintain current knowledge.

Challenges and Inconsistencies in Germline Testing Guidelines

Consensus guidelines for germline genetic testing, while well-intentioned, face significant challenges. Despite best efforts to maintain currency, guidelines cannot be refreshed as rapidly as new literature emerges. Furthermore, guidelines from different organizations often conflict, creating confusion about testing indications.

Colorectal Cancer Testing Guidelines: A Case Study in Variability

Guidelines for colorectal cancer demonstrate substantial variability across organizations. NCCN recommends genetic testing for colorectal cancer diagnosed before age 50, multiple primary cancers, Lynch syndrome, mutation probability greater than 2.5%, or specific polyp counts (10-19 polyps at ages 40-49, or more than 20 at any age). However, other guidelines differ significantly from these criteria.

The American College of Medical Genetics prefers multi-gene panel testing for inherited colorectal cancer and polyposis syndromes, with testing recommended based on clinical and family history. The American Society of Clinical Oncology (ASCO) recommends mismatch repair or MSI testing for all colorectal cancers, with panel testing recommended when Lynch syndrome is suspected.

Breast Cancer Testing Guidelines

Breast cancer guidelines show somewhat more consistency. The American Society of Breast Surgeons recommends testing for all breast cancer patients, a recommendation that also applies to ovarian cancer, pancreatic cancer, and metastatic prostate cancer. Nevertheless, these guidelines remain complex, requiring clinicians to remember every indication for each patient or navigate pre-authorization processes for insurance coverage.

The INSPIRE Study: Revealing Limitations of Current Guidelines

To assess what NCCN guidelines miss, the INSPIRE study (Implementing Next-Generation Sequencing for Precision Intervention and Risk Evaluation) was created based on the belief that universal access to germline genetic testing represents the unequivocal future of cancer care. The study provides no-cost germline genetic testing to patients as part of a research protocol designed to generate data supporting universal testing implementation.

INSPIRE Study Design and Methodology

The INSPIRE study is a prospective cohort study designed to determine uptake, diagnostic yield, patient experience, and outcomes of expanded access to comprehensive multiplex panel testing. The testing panel includes 154 cancer genes and 49 ACMG (American College of Medical Genetics) actionable genes.

Activated in July 2020, the study returned results to more than 20,000 patients by a planned interim analysis in May 2024. The patient population reflects City of Hope demographics, with very few patients declining participation. Only 7% declined, primarily citing the need to focus on their cancer diagnosis. Others deferred, requesting later contact. Overall participation reached 83%.

Ninety percent of participants were cancer patients, predominantly with breast and prostate cancers. Many patients had multiple primary cancers, with colorectal and lung cancers also well-represented. Approximately 10% of participants were unaffected individuals.

INSPIRE Study Results: High Diagnostic Yield

Results revealed that 17% of participants tested positive for either a cancer gene or an ACMG actionable gene, excluding recessive carriers. This figure underscores the value of identifying recessive gene carriers for reproductive planning purposes.

Breast cancer represented the largest diagnostic category, with multiple primary cancers also common. Testing was offered to unaffected individuals seeking preventive care and at-risk relatives. The mutation distribution reflected breast cancer's predominance, with BRCA1, BRCA2, ATM, CHEK2, and PALB2 ranking highest. Monoallelic carriers of genes like MUTYH and BLM were also identified.

Gene distribution analysis categorized findings into high-risk, moderate-risk, low-penetrance genes, and recessive carriers, organized by syndrome-specific identification rates. Cancers of the eye or orbit showed the highest detection rates, unsurprisingly revealing RB1 mutations in children with retinoblastoma. Conversely, liver cancer, predominantly viral in origin, showed lower germline mutation prevalence, though not zero. One liver cancer patient carried a BAP1 mutation, another an SDHA mutation, demonstrating the value of comprehensive testing across all cancer types.

Critical Finding: NCCN Guidelines Miss 69% of Mutation Carriers

Genetic counselors reviewed every positive case to determine whether patients met NCCN criteria at the time of testing. In the INSPIRE study, where 15% of 20,000 participants tested positive for a cancer gene and 2.3% for an ACMG actionable gene, NCCN guidelines demonstrated only 31% sensitivity. This means 69% of patients with pathogenic mutations would not have qualified for germline genetic testing under current guidelines, a striking false negative rate that clearly indicates the need for guideline revision.

Colorectal Cancer Findings in INSPIRE

High-penetrance variants in colorectal cancer patients revealed expected genes, including mismatch repair genes and APC, as the most commonly mutated. However, unexpected findings included BRCA1, BRCA2, SDHD genes, TP53, and even tuberous sclerosis. Nearly 19% of colorectal cancer patients carried pathogenic mutations, highlighting the importance of comprehensive panel testing.

Lynch Syndrome Detection Across Cancer Types

Lynch syndrome was identified across multiple cancer types: approximately 3% of colorectal cancer patients, 2.5% of endometrial cancer patients, just under 1% of gastric cancer patients, 1.1% of ovarian cancer patients, and 0.8% of pancreatic cancer patients. Identifying Lynch syndrome across these diverse malignancies proves critical for therapeutic decision-making.

Clinical Impact of Germline Testing on Cancer Therapy Selection

Lynch Syndrome and Immunotherapy Response in Colorectal Cancer

A 33-year-old woman diagnosed with stage IV sigmoid colon adenocarcinoma presented following resection and primary anastomosis. She unequivocally qualified for germline genetic testing due to her young age and strong family history of breast, colon, and cervical cancer. Testing revealed an MSH6 mutation.

She started combination ipilimumab and nivolumab therapy, achieving a near-complete response after two months of combination immune checkpoint inhibitor therapy. She then proceeded to nivolumab maintenance alone, with no evidence of disease after one year of therapy. At her last follow-up four months after stopping therapy, she remained disease-free.

Another case involved a 48-year-old man diagnosed with stage III cecal adenocarcinoma. Germline genetic testing identified a PMS2 pathogenic variant. After receiving adjuvant therapy, he developed recurrent metastatic disease approximately one year after diagnosis and started pembrolizumab. Six months after starting therapy, he showed no evidence of disease, remaining disease-free two years after pembrolizumab initiation.

Analysis of 44 Lynch syndrome patients from approximately 1,000 reviewed charts revealed treatment patterns across up to six lines of therapy. Immunotherapy was introduced at various stages—first line, second line, third line, fourth line, and fifth line—with many patients achieving and maintaining no evidence of disease status.

BRCA1/2 and Hereditary Breast and Ovarian Cancer Syndrome

BRCA1 and BRCA2 mutations showed significant prevalence across multiple cancer types. Nearly 4% of breast cancer patients carried BRCA1 or BRCA2 mutations, 11% of ovarian cancer patients, and 3.5% of pancreatic cancer patients. All these patients qualify for PARP inhibitor therapy, representing a substantial therapeutic opportunity.

Li-Fraumeni Syndrome: An Under-Recognized Condition

Li-Fraumeni syndrome remains significantly under-recognized in clinical practice. Without actively looking for it, it will not be found. TP53 germline testing proves particularly important in sarcoma, breast, brain, lung, leukemia, and adrenal cancer patients.

A critical caveat applies when assessing TP53 mutation prevalence in leukemia: clonal hematopoiesis of indeterminate potential (CHIP) can bias results. Patients who received previous chemotherapy may acquire somatic TP53 mutations detectable in blood-based testing that are not truly germline, distinguishable by allele frequency differing from the expected 50%.

Identifying specific TP53 mutations has direct therapeutic implications. For example, patients with Y220C TP53 mutations may qualify for clinical trials testing mutation-specific targeted therapy designed to reactivate TP53 function.

Von Hippel-Lindau Syndrome and Targeted Therapy

Von Hippel-Lindau syndrome research, which elucidated the gene's role in oxygen-sensing mechanisms and earned the Nobel Prize several years ago, led to belzutifan development.

A 67-year-old man presented with multiple enhancing lesions within the thecal sac involving the thoracic and lumbar spine, causing left leg weakness and numbness, and intractable left-sided body pain. He also had a large hemangioblastoma at C5-C,6 causing neck pain, with only modest symptomatic relief from Norco, gabapentin, and acetaminophen. Initially, he did not qualify for germline genetic testing under standard guidelines.

However, through the INSPIRE study, testing revealed von Hippel-Lindau syndrome with a pathogenic VHL variant, qualifying him for belzutifan therapy. Four years after starting belzutifan, his pain is well-controlled, tumor size has decreased, and pain has significantly improved, demonstrating the profound therapeutic impact of germline information.

Unexpected Clinical Applications: RUNX1 and Chemotherapy Administration

A 65-year-old woman with ovarian cancer experienced disease progression, but her oncologists faced treatment constraints due to persistently low platelet counts, causing concern about administering chemotherapy due to thrombocytopenia risk.

Panel testing revealed a RUNX1 variant, which causes thrombocytopenia. She had RUNX1 familial platelet disorder with associated myeloid malignancy risk. Her platelet counts would never reach normal levels. Once this was understood, chemotherapy could be safely administered with the knowledge that therapy should not be withheld for a woman whose platelet count would always remain low. Unnecessary treatment delays and discontinuation had adverse consequences over time, but this genetic information fundamentally changed her care approach.

Future Directions for Germline Testing in Oncology

Returning to the three initial goals: recognizing indications for germline genetic testing based on consensus guidelines remains necessary for insurance reimbursement unless clinical trials are available, but guidelines are demonstrably limited. The clinical utility of germline genetic testing extends beyond preventive care to therapy selection, with multiple FDA-approved indications.

Panel size matters significantly. The era of single-gene testing should be over, with comprehensive panels becoming standard practice. The optimal panel size—what constitutes too large, too small, or just right—remains an important discussion topic.

Consensus guidelines must evolve based on data from studies like INSPIRE and others, including work from Mayo Clinic and United Kingdom investigators, demonstrating improved sensitivity with universal access to genetic testing.

In conclusion, indications for germline genetic testing remain complex and inconsistent, largely driven by tumor type, age of onset, and family history. The clinical utility of germline genetic testing for therapy selection continues to expand with numerous approved FDA indications. Universal access to germline genetic testing represents the future of precision oncology, promising to identify more patients who can benefit from targeted therapies and preventive interventions while improving overall cancer care outcomes.