Abstract
The development of comprehensive genomic profiling (CGP) for cancer has flowed as a natural progression from the combination of more powerful and less costly next-generation sequencing, along with research that continues to identify new genetic drivers of disease. Single marker tests soon became broad panels of dozens of genes, which grew to today’s CGP panels containing hundreds of genes able to provide DNA and RNA sequencing data, readings for microsatellite instability (MSI)-high and tumor mutational burden (TMB), and more complex signatures such as homologous recombination deficiency (HRD).
This evolution has also followed a path that redefines how researchers, drug developers, and clinicians view cancer and how to treat it. “Cancer care is evolving from an organ-based treatment to biology-based treatment decisions and CGP is foundational to this shift,” said Rick Baehner, MD, chief medical officer of precision oncology at Exact Sciences.
The most common driver mutations, like those in TP53, EGFR, KRAS, PIK3CA, and APC, are well known and present across a range of solid tumor types such as non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer, prostate cancer, and melanoma. Many of these mutations driving cancers in different organs have a range of targeted therapies, allowing CGP to more precisely match a patient with NSCLC and an EGFR mutation with a tyrosine kinase inhibitor or a breast cancer patient with BRCA mutations with poly (ADP-ribose) polymerase (PARP) inhibitors.
Ezra Cohen, MD
Chief Medical Officer
Tempus Labs
Luca Quagliata, PhD, global head of medical affairs at Thermo Fisher Scientific, notes that development of targeted drugs for cancer is only half the story of improving patient outcomes. “There is no precision medicine unless there is precision in diagnostics,” he said. “You can have the best drug in the world, but if you don’t have the way to connect it with a patient, it’s a miss.”
In addition to CGP enabling more precise patient–drug matching, these tests are providing value in other ways, like informing the detection of minimal residual disease (MRD) to allow earlier treatment of recurrent and metastatic disease, when therapies are known to be most effective.
That said, it is a technology that continues to evolve and mature. “There is still so much to do and discover,” said Ezra Cohen, MD, chief medical officer of oncology at Tempus Labs. He noted that currently there are a range of cancers driven by fusions or other alterations that do not have targeted therapies, but have some are on the horizon. “There will be a need to add those events to routine testing,” Cohen added, noting that “we are just beginning to understand the complexity of epigenetic and post-translational modifications which will have prognostic and therapeutic implications in the near future. These will require completely different assays than we routinely use now. Believe it or not, we are just scratching the surface.”
Increasing utility of CGP
The effectiveness of CGP has made the most impact to date for informing NSCLC treatments. This early utility was driven by guidelines from the American Society of Clinical Oncology and National Comprehensive Cancer Network that encouraged broad biomarker testing in advanced disease to reveal actionable mutations that could be addressed with targeted therapies.
But Baehner noted that CGP now influences treatment decisions in many of the most common—and most lethal—cancers. “We are just seeing it across the board,” he said, noting that breast cancer and colorectal cancers are seeing a steady increase in discovery of actionable biomarkers pointing toward targeted treatments.
Breast cancer is also highlighting the importance of CGP to drive earlier treatment decisions. The OlympiA clinical trial of olaparib in patients with HER2-negative breast cancer with BRCA1 and BRCA2 mutations showed that they benefitted from the drug in the adjuvant setting. Its approval for earlier treatments means that CGP now plays a role in identifying this cohort of patients, with data showing that treating them directly after frontline interventions such as surgery or radiation therapy lowered the risk of death by as much as 32% in the ensuing years.
Importantly, as CGP testing has evolved, it has not remained confined to simply looking for known single nucleotide variants. Over the past 10 years, hybrid panels have emerged to capture insertions and deletions (indels), copy number variants, and structural variants. More complex signatures for TMB and MSI-high, now included in these assays, can inform the selection of immunotherapies.
The past five years have seen even more advances that include RNA-seq to improve detection of fusions and splice variants. As Baehner noted, sequencing RNA “tends to be associated with a 15 to 20% higher likelihood of identifying fusions,” while also providing a clearer snapshot of tumor activity. “DNA tells you what could happen. RNA tells you what is happening, what pathways are turned on.”
Cohen added that research by Tempus has shown the importance of matching both DNA and RNA sequencing in tumor tissue in combination with germline tasting to improve diagnostic accuracy. “In addition, our data would suggest that about 9% of alterations will only be found in ctDNA (circulating tumor DNA), so it is important to order both tumor and blood simultaneously,” he said.
Rick Baehner, MD
Chief Medical Officer
Exact Sciences
Other advances include identifying hybrid signatures for biomarkers like HRD and genomic loss of heterozygosity, which can help guide PARP inhibitor treatments. “We are now talking about integrating a single biomarker or single gene status together in the context of a signature, a complex biomarker,” Quagliata said, while adding that he believes the next five years will see even more significant changes.
“In these last five years, there’s been a lot of new drugs that hit the market,” he noted, pointing to the development and approval of PARP inhibitors. “CGP testing has shown that (HRD, whether driven by BRCA1/2, other HRR (homologous recombination repair) gene alterations such as PALB2, ATM, or characteristic genomic-scar signatures, is the key determinant of clinical sensitivity to PARP inhibition. Notably, BRCA-negative patients who are HRD-positive may indeed still benefit from such drugs.”
Further, while PARP inhibitors were initially approved for ovarian cancer, now they are also used in breast and prostate cancer, with bladder cancer likely the next indication to benefit. This means that the utility of CGP will take on more importance for matching treatments. And that is just an example of one biomarker signature. Similar expansion is anticipated in other classes of drugs addressing other molecular profiles.
Emerging clinical evidence
As the technology for CGP has become more refined, the focus has shifted to clinical utility with an eye toward increasing adoption by physicians and, in the U.S., broader reimbursement by payers. Research has also focused on identifying when providing CGP is most effective.
There is emerging evidence that providing CGP earlier in a patient’s treatment journey, often directly after immunohistochemistry has positively identified a solid malignancy, has significant clinical benefit. In ongoing research conducted by Providence Health in Portland, OR, a clinical study has shown that providing early, pathologist-directed CGP helped inform more targeted treatments, which led to longer median survival for patients with cancer.
Carlo D. Bifulco, MD
Chief Medical Officer
Providence Health
The research, published in late 2024 in the Journal of Clinical Oncology–Oncology Practice, presented the first two years of data from a five-year research project created to provide evidence of the clinical impact of CGP compared with standard tumor molecular testing. To date, the researchers have generated data evaluating a 523-gene DNA/RNA hybrid CGP panel that is ordered as standard practice by pathologists at the time of initial cancer diagnosis. The intent was to compare how treatment decisions—and outcomes—varied by ordering a broader panel directly after a solid tumor diagnosis, and comparing how treatment selection varied from decisions made based on information provided by a targeted 50-gene panel.
“The pathologist-directed protocol addressed a fundamental timing problem in oncology care,” said Carlo D. Bifulco, MD, chief medical officer of Providence Genomics and a co-author of the study. “In the traditional workflow, genomic testing was ordered downstream—often after conventional therapies had failed. By then, patients were already on a treatment trajectory that might not reflect their molecular profile.”
This realignment of when to order testing is central to how CGP could fundamentally change clinical practice, Quagliata noted.
“There is no precision medicine, unless there is precision in diagnostics. It’s about connecting the right patient with the right drug at the right time,” he said. “You can have the best drug in the world, the most effective drug, but if you don’t have a way to connect it to the patient, it’s a miss.”
In the Providence Health study, working with diagnostic partner Illumina, next-generation sequencing results were available a median of 12 days before the initial medical oncology patient visit. This was much earlier than conventional testing results, which are often delivered on the day of the patient visit or even after. The study showed that having genomic data in hand at the first consultation led to more than half of the patients receiving biomarker-informed targeted therapy or immunotherapy, rather than physicians defaulting to standard-practice chemotherapy, radiation, or both.
The first two years of collected data presented a compelling picture of the utility of early CGP. Among the 3,216 patients with advanced solid tumors, CGP identified actionable alterations—defined by guideline-recommended therapies or eligibility for clinical trials—in 67% of patients’ tumors. This compares with only 33% of cases with actionable alterations uncovered by the 50-gene panel used in the study. In addition, TMB-high status, present in 22% of patients, was identified as the most common actionable biomarker, a measure not available on small gene panel tests.
“The most significant finding was TMB-high, which you simply cannot assess reliably without broad genomic coverage,” Bifulco said. “Beyond that, CGP captured rare but targetable alterations—such as NTRK fusions—that are easy to miss but can be transformative for individual patients.”
The early findings from this ongoing study indicated that providing CGP soon after initial diagnosis had a meaningful impact on both treatment decisions and clinical outcomes. Among patients with at least six months of follow-up, 52% received a targeted therapy or immunotherapy guided by their CGP, reducing the number of patients who received only chemotherapy. Median overall survival also improved to 25 months for patients treated with targeted therapy informed by CGP, compared with 17 months for those treated with chemotherapy. Similar trends were shown in cancer-specific cases, such as NSCLC, where CGP-tested patients lived a median of 16 months versus seven months for patients tested with a smaller NSCLC-targeted panel.
While the study is ongoing, the early results paint a clear picture to Bifulco. “Our data strongly support early CGP as standard of care for advanced solid tumors,” he said. “This represents a genuine paradigm shift—precision therapies and immunotherapies have overtaken conventional chemotherapy in this early-tested population.”
CGP also showed utility in identifying carcinomas of unknown primary—instances when a definitive diagnosis was not possible. Further, having a pathologist at the center of decision-making can reduce the variability created by individual physician ordering habits and patient self-advocacy. Establishing it as the norm was shown to help ensure more uniform access to precision medicine.
While the early data is encouraging, the authors noted there are obstacles to the adoption of such an early CGP program. For their research purposes, all CGP testing was provided at no cost to patients. The Providence study thus eliminated one of the largest barriers to CGP access in the U.S.—whether payers would provide reimbursement for these services. “We hear more and more from treating physicians that they just can’t keep pace with how quickly the space is moving, whether it’s the diagnostic space or therapies.”
“Reimbursement is the hardest barrier,” Bifulco said. “The cost differential between CGP and small panels is modest, relative to the cost of cancer therapies, but until coverage is consistent, adoption will remain uneven and socioeconomic disparities will persist.”
Bringing CGP to the community setting
While academic medical centers are often the sources of advances in precision oncology, it is adoption of these tests by oncologists working in the community setting that will benefit the most patients. “Roughly 80% of patients are treated in the community,” said Warren Stone, president and chief operating officer of NeoGenomics. “They want to be close to their support systems, their infrastructure, when they’re going through one of the most defining periods of their lives.”
Bringing these capabilities to areas outside large urban regions and away from the academic medical centers is NeoGenomics’ focus. Achieving this will make access to targeted treatments available to the many and not just the few, while helping avoid ineffective treatments and their adverse effects.
Despite the known benefits of CGP, fostering wider adoption is difficult. “We hear more and more from treating physicians that they just can’t keep pace with how quickly the space is moving, whether it’s the diagnostic space or therapies,” Stone noted. Reimbursement issues also hamper adoption. While there are clear guidelines to encourage its use to provide targeted treatments in NSCLC, the lack of consensus in other malignancies has payers, including Medicare, largely on the sidelines.
Community oncologists, Stone added, “are often focused on making sure the patient isn’t subjected to undue expenses. Knowing [CGP] will likely be an out-of-pocket expense is an adoption limitation.”
Regardless, the company actively seeks to educate physicians in the community setting on the benefits of CGP to foster broader adoption, starting with the company’s sales team to medical science liaisons who provide peer-to-peer information with a focus on education. The most effective efforts by the company come from a small handful of key opinion leaders, treating physicians who share real-world cases and outcomes. “This is hearing from somebody who is experiencing the same challenges on a day-to-day basis,” Stone said.
Early CGP aids MRD
Increasingly, the early application of CGP is playing a role in MRD detection to help clinicians get a jump on recurrent or metastatic disease. Having the deep and detailed understanding of the molecular landscape of a patient’s cancer that CGP can deliver is a vital tool for monitoring their treatments.
“I need to understand what’s happening at the first diagnostic pass,” Quagliata said. “So I do a CGP because I try to get the overall picture, as big as I can.” This initial molecular snapshot provides the biological context clinicians can call on when monitoring patients and deciding on next treatments should the cancer return.
Baehner echoed this idea, noting that having the data on the initial tumor is a vital first step. “Those mutations are very relevant for tumor-informed MRD tests,” he said, with subsequent monitoring conducted using a liquid biopsy via ctDNA to determine whether there are remnants of disease after the first treatment. If ctDNA is detected, “those patients, across multiple studies, are shown to have a very high risk of recurrence.”
According to Stone, informing MRD with a broad initial assessment of a patient’s tumor is key to evolving cancer care, from treatment of an acute terminal disease toward chronic disease management. “This is an entire journey to make treatment personal, and I think that’s the future of oncology,” he said. “I think there’s going to be a rapid adoption of MRD, to be able to detect whether cancer is returning significantly earlier than you can identify through scans. Because this allows for less invasive treatment options and that’s great news for patients.”