Precision oncology continues to expand at a rapid rate in oncology, leaving several gray areas for interpretation and application of currently available data, which represent a unique opportunity for pharmacists, according to a panel discussion at the 2023 HOPA Annual Conference. To help shed light on common scenarios, the panelists reviewed 6 patient cases, and discussed unique considerations for each case.

Experts discuss precision medicine at annual HOPA conference. Credit: auntspray - stock.adobe.com.

“Pharmacists are well positioned to have an integral role in precision oncology and molecular tumor board, based on our developed skill sets,” panelist Ni-Chi Wu, PharmD, BCOP, BCPS, National TeleOncology clinical pharmacy specialist and National Precision Oncology Program

consultant, Veterans Health Administration, said during the session. “Molecular tumor boards are easier than ever to be involved in, since a lot are virtual or asynchronous, and many pharmacists are now participating at their institutions.”

Data should inform decisions, and one of the largest gaps in precision medicine is a lack of data across diverse patient populations, given low diversity in clinical trials, Wu said. Differences in genomic profiles have been observed by race, and clinical trial enrollment typically underrepresents minority populations.

Another gap to precision medicine is the process itself, Wu noted, adding that nearly 50% of patients are lost in the precision oncology pathway before achieving a result. The most frequent gaps are seen when ordering the test (18.1%) and at the treatment decision step (29.2%), perhaps due to a lack of ability to interpret the findings, according to findings published in JCO Precision Oncology. Wu also noted that overall awareness of precision techniques and insurance coverage also adds to these barriers.

To improve on these challenges, Wu suggested standardization, as well as a consistent pathway and algorithm for precision medicine treatments. Another opportunity is through expanded access to care, which is coming about through telemedicine in many communities. The final item comes down to more educational opportunities, Wu said.

Testing Guidelines

The first step to precision medicine is knowing when and how to complete comprehensive genomic profiling (CGP), suggested Jennie Piccolo, PharmD, BCOP, National Precision Oncology Program consultant, William S. Middleton Memorial Veterans Hospital. In both cases, guidelines exist, with the panelists drawing attention to the ASCO molecular testing and biomarker guidelines and National Comprehensive Cancer Network (NCCN) guidance within each tumor type. NCCN also has a biomarker compendium, Piccolo said.

Across guidelines, CGP is recommended when it will impact the treatment decisions or when a specific genomic-based biomarker could lead to a contradiction or exclusion. Additionally, the panelists noted, it should be considered for determining eligibly for clinical trial participation. These scenarios typically occur early in the diagnosis, with a few scenarios also calling for retesting in the case of acquired resistance mutations.

“Testing is recommended for most metastatic and advanced cancers,” Piccolo said. “ASCO prefers multigene genomic sequencing whenever eligible and NCCN recommends a tumor specific test or a must-gene panel, when it is recommended for that disease.”

Although a tissue biopsy is the gold standard for obtaining a sample for CGP, it can often be hard to obtain. Additionally, there may be potential for sampling bias due to heterogeneity.

Given these limitations, liquid biopsy has grown in popularity because it can be conducted with a simple blood draw and is representative of the whole tumor. An effective paradigm may be to complete a tissue biopsy upfront with subsequent liquid biopsies at the time of progression, if indicated, according to the panel.

“You want to make sure the timing of the liquid biopsy is optimized prior to treatment for when progressing to maximize diagnostic yield,” Piccolo said.

Those with a high tumor burden and progressive disease are ideal candidates for liquid biopsy, she added, whereas those on treatment with a low tumor burden are not ideal candidates, as there may not be ample amounts of circulating tumor cells.

Case Scenarios Uncover Common Pitfalls

In the first case study presented, a 68-year-old patient with metastatic adenocarcinoma of the lung received CGP at initial diagnosis, which revealed no actionable alterations. The patient eventually progressed, after receiving chemoimmunotherapy induction and maintenance. For this scenario, the speakers polled the audience on whether they would pursue additional testing at the time of progression, with mixed results.

Overall, approximately two-thirds of the polled attendees said they would forego additional testing, as the original test was sufficiently informative, and they did not believe additional actionable information was likely to be found. However, nearly one-quarter of the attendees said CGP should be conducted for all progressions, but the utility of that approach is unclear.

“This is where we really need to balance resources,” added Christine M. Walko, PharmD, BCOP, FCCP, senior member, Department of Individualized Cancer Management, Precision Medicine Program lead and Precision Medicine Clinical Service attending, Moffitt Cancer Center, alluding to the costs associated with testing. In addition to finding actionable alterations, there are other reasons to test, she added. It can be used to detect recurrence in some scenarios, particularly in colorectal cancer.

Another reason to retest is if a second primary tumor is suspected, according to Piccolo.

The next scenario described was a 66-year-old with stage IV squamous cell lung cancer that had metastasized to the liver and lymph nodes. The patient was initially diagnosed with stage I disease, underwent surgical resection, and progressed. After this, they were started on chemoimmunotherapy followed by maintenance pembrolizumab.

On progression, next-generation sequencing (NGS)-based liquid biopsy was completed, which revealed RET V778I, with a variant allele frequency (VAF) of 1.2%. The oncologist, based on this finding, wished to initiate selpercatinib (Retevmo).

This scenario called into question the significance of findings on the test results, with panelists noting that somatic mutations are typically seen at a VAF of less than 50% whereas anything over this count should be a sign of a germline mutation. Moreover, they discussed tumor purity, as it relates to the percent of cancer cells in the sample and the method for detection. Together, the lower VAF and unknown methods for detection (machine vs pathologist) or tumor purity, led the audience and panelists to agree that more information was needed on the RET status before initiating targeted therapy.

Given the low VAF, this RET finding was labeled as being of unknown significance, which is 1 of 4 tiers created in 2017 to help interpret CGP results. In this system, the first tier represents clearly detected variants with an FDA-approved therapy.

Tier 2 includes those with a targeted therapy approved for another indication with some small study data showing a potential benefit. Tier 3 are variants of unknown significance, which is typically the largest group detected. Tier 4 are benign variants, with no known connection to cancer.

From here, the panelists moved into the third case study, a 60-year-old with adenocarcinoma of the prostate, previously treated with leuprolide, radiation therapy, and abiraterone acetate (Zytiga) plus prednisone. A previous NGS test from a liquid biopsy revealed an ATM E770 alteration at a VAF of 0.12%. Based on this finding as a gene associated with homologous recombination repair, the oncologist wished to pursue treatment with olaparib (Lynparza).

The challenge associated with this case, as Wu described, was the occurrence of clonal hematopoiesis of indeterminate potential (CHIP) on liquid biopsy, a scenario in which somatic mutations are seen in the blood or bone marrow, even without the presence of cancer. This occurs as a normal part of aging, Wu noted.

In most cases, if the VAF is less than 1%, CHIP should be considered, she added, noting that ATM is a common alteration identified for CHIP interference.

“One way to get around CHIP is to pair cell-free DNA testing with whole blood or tumor tissue results,” Wu noted. Given this information, 100% of those answering the audience response quiz said they would not give olaparib in this situation, given the questionable actionability of the ATM alteration detected.

The next scenario identified a 68-year-old patient with a poorly differentiated large cell neuroendocrine carcinoma of the bladder. This patient received carboplatin, etoposide, and atezolizumab (Tecentriq) with a tissue biopsy taken at the time of resection. The patient responded favorably to the platinum-based therapy.

Overall, CGP identified ATM loss, 3 unique BRCA2 alterations (each with a VAF >50%), and KRAS alterations (VAF of 50%), along with a loss of heterozygosity (LOH) of 20%. In this patient, the question proposed was whether to offer off-label olaparib, based on findings seen in ovarian cancer.

Loss of heterozygosity (LOH) of greater than 16 is typically indicative of response to PARP inhibitors, primarily from data derived from ovarian cancer, Walko noted. There are limited neuroendocrine data for olaparib, she added, with just 1 case study reported with a positive complete response.“Our goal, when we do these clinical consults, is to give the options to the treatment team, so they can weigh the options for the other treatment options that we have,” said Walko.

Eighty-two percent of the audience said they would offer olaparib as an option, which is what the patient did receive, Walko noted, along with atezolizumab. Thus far, the patient is doing well overall, she added.

In this scenario, Walko also suggested germline testing, particularly given a family history of cancer that was also observed and the high VAF. The panelists noted that the role of LOH remained unclear outside of ovarian cancer, suggesting additional studies in this area were warranted.

The fifth case was a 72-year-old patient with an unknown primary and a tumor mutation burden (TMB) of 30 muts/mb. Other findings included BRAF L597R and KEAP1 H274fs*3. Based on the TMB, most of the audience leaned toward treatment with pembrolizumab (Keytruda), although the panelists noted that TMB is a poor predictive biomarker for immunotherapy. Moreover, presence of a KEAP1 gene could lead to higher detected levels of TMB. In this scenario, based on the CGP findings, cisplatin plus etoposide would have also been an acceptable option, Walko noted.

The final case was a 42-year-old female with sigmoid colon cancer, representing a growing trend of younger patients receiving colon cancer diagnoses, Walko said. In this case, the patient was diagnosed with an existing liver metastasis. IHC testing indicated they were MMR proficient, but germline testing showed pathogenic heterozygous MSH2 E101_V102del, a signal of Lynch syndrome.

With the microsatellite stable (MSS) status, the colon cancer in this individual may have been related to another factor, beyond the Lynch gene, the panelists noted. If MSI had been high, immunotherapy would have been an ideal treatment. In some cases, however, immunotherapy has shown some promising results even in patients with MSS Lynch-positive phenotypes.

In genetic testing, there were no BRAF, KRAS, or NRAS alterations. For this patient, 92% of the audience felt chemotherapy plus either bevacizumab or cetuximab was the ideal option.

“She did end up getting pembrolizumab later, but progressed through it very quickly,” said Walko.

The panelists closed the session by reiterating the fast pace of change in the precision oncology field, stressing the important role that pharmacists should continue to play.

“Precision oncology is an ever-growing, ever-changing field requiring critical analysis of results and treatment options,” Walko said.

Reference

Piccolo J, Walko C, Wu N. Controversies in Precision Oncology: Interpreting the Grey Areas. Presented at 2023 HOPA Annual Conference. March 30, 2023.