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Translating Cancer Genetics into Clinical Practice

JHOP - June 2019 Vol 9, No 2 - HOPA Highlights
Meg Barbor, MPH


Genetic alterations in molecular pathways are involved in tumor development, survival, and progression. Precision cancer medicine is about using the cancer genome to guide treatment decisions, according to Christine M. Walko, PharmD, BCOP, Personalized Medicine Pharmacologist, Personalized Medicine Clinical Service, and Chair, Clinical Genomic Action Committee, Moffitt Cancer Center, Tampa, FL. She discussed the role of cancer genome into clinical practice at the 2019 Hematology/Oncology Pharmacy Association (HOPA) annual meeting.

“We know that genetic alterations in molecular pathways make tumors grow,” Dr Walko said. “We have the technology to profile it, and we have drugs—on-label, off-label and in clinical trials—that we can utilize to target these profiles.”

“It’s not just about the gene; it’s about the mutation that could be driving the cancer,” she said. Therefore, it is important to distinguish between the mutation that could be driving the cancer and the mutations that should not be targeted (ie, passenger mutations and benign germline mutations).

According to Dr Walko, tumor genomic interpretation should address the following questions:

  • Does the gene mutation provide information about prognosis?
  • Does the gene mutation provide information of predicting response or resistance to therapy?
  • What is the strength of evidence and patient characteristics to consider for treatment prioritization?

Not all mutations in known oncogenes are pathogenic, she said, but the gene combined with the mutation could be pathogenic. For example, BRCA2 is a known tumor suppressor gene that is pathogenic when inactivated (ie, BRCA2 C1159), but some alterations can be benign (ie, BRCA2 K3326).

“The big things that we’re looking for are driver mutations—tumor suppressor genes that are getting turned off and oncogenes that are getting turned on,” Dr Walko said. “We want to separate those out from passenger mutations.” Passenger mutations do not have an effect on a cell’s growth and are less clinically relevant.

Prognostic and Predictive Variants

Prognostic variants represent the underlying biology of the tumor and provide information about cancer outcomes, independent of treatment. For example, the TP53 mutation in chronic lymphocytic leukemia is associated with poor progression-free survival.

Predictive variants provide information about response to a specific treatment; for example, activating EGFR mutations are associated with increased response to EGFR inhibitors, such as erlotinib or gefitinib.

However, some biomarkers can be prognostic as well as predictive if they predict outcomes and response to therapy.

“We’re looking for clinical actionability,” Dr Walko said. Actionability can be characterized by a genetic alteration that predicts a response to a certain therapy, or provides diagnostic or prognostic information, or by a clinically relevant germline alteration that informs disease risk. Or, perhaps, actionability means looking into a clinical trial that is available for a patient’s particular alteration, she explained.

Off-Label Drug Acquisition

According to Dr Walko, the success of a patient getting off-label drug therapy depends heavily on his or her type of insurance.

“We try to write our patient consults so that we can use them to get off-label drug therapy by including information about the genetic mutation, an explanation of the human data and the citations,” she said. “They want to see human data, even if it’s just one case. Then it’s about having the patience and the time to go back and forth with the insurance company and convince them.”

Challenges in Precision Medicine

“We do see germline mutations bleed into our tumor interpretations,” Dr Walko said. If a tumor is analyzed with matched normal, healthy tissue, the alterations found in the normal tissue can be subtracted out. But commercial tests do not compare the 2 types of tissue, and if normal tissue is not analyzed, it is much more difficult to distinguish between cancer cells and healthy cells.

“So everything occurring in the germline gets pooled in with the cancer cells,” she explained. “In some cases, like with a germline BRCA mutation, we do want to target it, but most of the time we’re just trying to subtract those out.”

Historically, precision medicine clinical trials occurred in large subsets of the population (ie, patients with HER2, BCR-ABL, or BRAF mutations). This enabled enrollment and completion of large-scale prospective studies, and demonstrated the clinical utility of the diagnostic marker (ie, BRAF V600E) and companion diagnostic tests, as well as the clinical efficacy of targeted drugs.

But, according to Dr Walko, the continued growth of precision medicine in oncology is faced with challenges. In rare mutations, diverse levels of evidence support the value of a genetic biomarker being associated with a response to a targeted agent, and rare mutations across tumor types make enrolling enough patients on a randomized study logistically difficult.

“This is why with ROS1 or MET, we’re looking at a phase 1 trial. Even if we tried, we couldn’t do a randomized trial with enough power, unless we had 20 years to do it, and by then, we’ve already missed the boat,” she said. “So we have to figure out right now, how to treat these patients and how to get this evidence.”

Basket and Umbrella Clinical Trials

Potential answers to these particular challenges include basket trials, which match specific genetic alterations to targeted therapy independent of disease histology (eg, the NCI-MATCH trial), and umbrella trials, which match specific genetic alterations to targeted therapy within the same tumor type (eg, the BATTLE trial in lung cancer).

Dr Walko noted that these types of clinical trials may produce lower levels of evidence. However, in general, precision medicine trials have shown benefit.

A multivariate analysis of 570 phase 2 clinical trials with a novel therapy that enrolled more than 32,000 patients showed that treatment allocated by personalized approach consistently and independently correlated with higher response rates, longer median progression-free survival, and longer overall survival than other studies.

“So we do know that these [trials] work; we likely just need better drugs for the targets that we’re assessing,” Dr Walko said.

Pharmacist-Led Molecular Tumor Boards

According to Dr Walko, pharmacists are well-positioned to play integral roles in molecular tumor boards. They have developed skill sets, including extensive experience with literature searching and the ability to integrate cancer biology with pharmacotherapy options. They have experience communicating with and educating patients, are able to assess clinical trials and consider inclusion and exclusion criteria, and can collaborate in symbiotic relationships with other vital members of the team, such as pathologists.

Pharmacist-led molecular tumor boards have been successfully implemented at the University of Wisconsin, Indiana University, and Moffitt Cancer Center in Florida. “And I’m certainly hoping that this list is continuing to grow,” Dr Walko said.

To be successful, a pharmacist-led molecular tumor board requires a multidisciplinary team of motivated individuals, including medical and hematology oncologists, pathologists (of all different shapes and sizes), bioinformatics, and basic scientists, she said. Team members will also need to be able to access literature and to collaborate with those who maintain the electronic medical records.

“And you need time,” Dr Walko added. “I would not be able to do what I do—and to have the enthusiasm that I do—if Moffitt didn’t support me in doing it. You really need to get your institution to believe in the value of this and support you.”

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