Gray Areas Exist in Proper Precision Medicine Application in Oncology

Drug Topics JournalDrug Topics May 2023
Volume 167
Issue 05

Precision oncology is a growing, changing field.

Precision medicine continues to expand as more targeted therapies with companion diagnostics receive FDA approval, warranting additional diligence when analyzing results of comprehensive genomic profile (CGP), according to panelists during a presentation at the 2023 HOPA Annual Conference.1

“Precision oncology is an ever-growing, ever-changing field requiring critical analysis of results and treatment options,” said Christine M. Walko, PharmD, BCOP, FCCP, from the Moffitt Cancer Center. The complexities of the process and analysis of the CGP results requires extra diligence on the part of treatment team, and pharmacist play a key role in this process, the panel noted.

One of the main barriers to precision medicine is the process itself, said Ni-Chi Wu, PharmD, BCOP, BCPS, Veterans Health Administration. Throughout each of the steps involved in getting genomic results, nearly 50% of patients drop out of the process before achieving a result, with only a minority of potentially eligible patients receiving targeted therapy. 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 and 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, such as sessions on the topic at medical conferences, said Wu.

The first step to precision medicine is knowing when and how to complete CGP. In both cases, guidelines exist, with the panelists drawing attention to the ASCO molecular testing and biomarker guidelines and NCCN guidance within each tumor type. NCCN also has a biomarker compendium, noted Jennie Piccolo, PharmD, BCOP, from the William S. Middleton Memorial Veterans Hospital.

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. Another aspect to consider is also clinical trial participation and availability, for specific genomic markers. 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,” said Piccolo. “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.”

While 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, as 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.

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

In some cases, particularly if the original tissue biopsy did not reveal an actionable mutation, a liquid biopsy at progression may not reveal additional findings. “This is where we really need to balance resources,” said Walko. This can vary depending on the type of malignancy and the goal of testing, she noted.

Once a test is obtained, additional challenges occur when interpreting the results. One common challenge is assessing the significance of the variant allele frequency (VAF). In most cases, 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, if only a small percent of the sample test contained cancer cells vs normal cells, this can also add uncertainty.

If the VAF percent on an alteration is low while the purity, or percent of cancer cells, is also low, the result may be 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.

Another consideration with VAF is the occurrence of clonal hematopoiesis of indeterminate potential (CHIP) on liquid biopsy, Wu noted. CHIP is a situation in which somatic mutations are seen in the blood even without the presence of cancer. This occurs as a normal part of aging, she said. 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.

The panelists also discussed loss of heterozygosity (LOH), which has been validated in ovarian cancer but has not yet received attention in other types of cancer. In ovarian cancer, LOH of greater than 16 typically indicates response to PARP inhibitors, noted Walko. With the absence of data in other disease, this data can be extrapolated, especially if there are case reports showing benefit.“Our goal, when we do these clinical consults, is to give the options to the treatment team, so they can weight the options for the other treatment options that we have,” said Walko.

Another common scenario is zeroing in on one actionable alteration but not considering the other alterations identified. In an example, the panelists noted a case of a tumor mutation burden (TMB) of 30 muts/mb along with a KEAP1 alteration. The initial assumption was that TMB would indicate a response to immunotherapy, but the KEAP1 alteration may confound this, as it can cause high TMB. Other examples of this may be the discovery of the Lynch syndrome gene MSH2 but the presence of microsatellite stability (MSS) and an intact mismatch repair. In both the case of TMB and Lynch, immunotherapy is indicated; however, KEAP1 and MSS could result in the treatment not being as effective.

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. “Pharmacists are well positioned to have an integral role in precision oncology and molecular tumor board, based on our developed skill sets,” said Wu.

1. Piccolo J, Walko C, Wu N-C. Controversies in precision oncology: Interpreting the grey areas. Presented at: HOPA 2023 Annual Conference; March 29-April 1, 2023; Phoenix, AZ.
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