Shopping Cart

INTRODUCTION

The era of targeted therapy began in earnest for hematology/oncology in 2001 with the approval of imatinib for the treatment of chronic myeloid leukemia (CML). This agent, which targets the binding pocket in the BCR-ABL tyrosine kinase domain induced by the chromosome (9;22) translocation that defines CML, ushered in a new era of precision medicine in cancer treatment.¹ The stunning positive results of the International Randomized Study of Interferon and STI571, or IRIS, trial that demonstrated clear superiority with imatinib over the standard therapy at the time (interferon and low-dose cytarabine) in both hematologic and cytogenetic remissions was a proof of concept that drug therapy could be designed to inhibit the net oncogenic effect of a specific cancer mutation.² This would serve to be a harbinger of a multitude of newly discovered mutations and newly developed targeted anticancer agents that would serve to change the landscape of cancer treatment both in hematologic and solid tumor malignancies over the succeeding two decades.

Pharmacogenomics is the study of how genetic differences between individuals influence the variability of drug response.³ As applied to medical oncology, this discipline has emerged from burgeoning success of genomic sequencing technologies for detecting somatic (acquired) mutations in tumor cells and the dynamic increase in anticancer drug approvals for agents directed at these mutations marking a new era of precision medicine.⁴ Medical oncologists, genetic scientists, pharmacists, pathologists, clinical nurse specialists, statisticians, and genetic counselors are now specializing in a new treatment paradigm, which uses this genomic information to tailor individualized therapy for cancer patients.

This continuing education module provides a primer for pharmacist regarding the emergence of precision genomics in the management of patients with oncologic disorders. Further, it presents case studies to highlight the real-world application of this relatively newfound clinical approach to unique patient circumstances to aid in the learners’ understanding. Lastly, the multiple roles that a pharmacist can play in an oncology precision genomics program are outlined.

GENOMIC SEQUENCING

Genetic findings in cancer have been employed to help guide treatment decisions in limited ways for several decades. The primary example of this is the use of cytogenetic abnormalities in acute leukemia, which helps hematologists decide which type of postremission therapy to prescribe based on the risk of relapse.⁵

Regarding the history of the application of genomic data, DNA sequencing became a reality in 1977 when Sanger and colleagues introduced a sequencing technology using specific chain-terminating nucleotides (dideoxy nucleotides, or ddNTP) that lack a 3'-OH group.⁶ This helped to establish the 3 basic steps involved to determine genotyping: first, DNA must be extract from a sample – in the case of cancer – it would be from a tumor sample extract from surgery or a biopsy. Secondly, laboratory procedures are employed to isolate the DNA from the cells of interest. Lastly, the DNA in the target cells is amplified using polymerase chain reaction (PCR) technology.⁷

The first-generation methodologies were considered to have a low sensitivity to detect short DNA sequences. The Sanger method is still widely used for individual reactions using a unique DNA primer for a specific template such as to verify plasmid constructs or PCR products; however, it is considered to be too costly and inefficient for widespread clinical use. The Human Genome Project, which was completed in 2003, led to an explosion of interest in using DNA-sequencing technology to combat a multitude of diseases.⁸

Next-generation sequencing (NGS), also referred to as second-generation sequencing, is a generic term for the development of a platform to sequence large genomes with high throughput technology.⁹ NGS can reliably detect DNA amplifications, deletions, rearrangements, fusions, and single nucleotide polymorphisms, which are known to be oncogenic drivers of cancer.¹⁰ NGS platforms can analyze up to approximately 600 genes with full exon coverage.¹¹ These platforms have become more efficient in sequencing just the regions of the genome that codes for proteins – exomes – which represents approximately 1% of the genome. One specific type of NGS — the methodology known as whole exome sequencing (WES) — focuses on identifying pathogenic genetic variants that can code for proteins known to be oncogenic without having to sequence the entire genome.¹² WES has gained popularity as a NGS platform of choice for clinical use due to its efficiency and cost compared to platforms that sequence entire genomes.

The specific genomic assays in the laboratory are tasked to characterize somatic (acquired) or germline (inherited) mutations in individual tumors. The identification of these mutations reveal the unique mutations, which could potentially be targeted for a specific drug.¹³ With an accumulating knowledge of mutational prevalence in different tumor types, new clinical trials can be designed that use a specific drug for a number of cancer diagnoses that harbor the same mutation. Use of genomic data derived from the patient being treated is taking on an increasingly important role in guiding medical oncology decisions for individualized drug treatment.

A number of novel clinical trials in precision oncology have been activated that seek to match a patient to the most appropriate therapy based on their tumor molecular profile. The National Cancer Institute Molecular Analysis for Therapy Choice, or NCI-MATCH, trial and the American Society of Clinical Oncology (ASCO) Targeted Agent and Profiling Utilization Registry, or TAPUR, trial are large, national trials that attempt to match a patient to an optimal therapy choice based on their tumor molecular profile.^14,15

MOLECULAR TUMOR BOARDS

A practical application to support more widespread use of genomic data in clinical decision making for cancer patient has been the development and implementation of molecular tumor boards (MTBs) at a number of academic medicals centers.¹⁶ These tumor boards generally have a membership of medical oncologists, genomic scientists, pathologists, genetic counselors, pharmacists, bioinformaticians, and other cancer or genetic experts. What distinguishes MTBs from a conventional tumor boards, is that the board will review clinical cases from a variety of different types of cancer diagnoses and will interpret genomic sequencing results often with multiple genetic variant interpretation databases to help guide clinical decision making.¹⁷ Other models that have been explored include establishing MTBs in a community oncology setting that may not have the expertise to convene MTBs and using teleconference and/or videoconferencing collaborate with a number of centers to reach a critical mass of skilled professionals.¹⁸

Established standards are available to guide clinicians in applying data garnered from genomic sequencing in clinical drug decision making for the treatment of cancer. Standards for medical professionals to interpret findings of somatic mutations in active cancer tumors have guidance issued by the Association of Molecular Pathology (AMP), ASCO, and the College of American Pathologists (CAP).¹⁹ To address the risk of inheritable disease that may impart the risk of developing cancer during one’s lifetime, biomarkers based on germline findings have standards that have been published by AMP and the American College of Medical Genetics.²⁰

In practical application, MTBs present a clinical summary of a cancer case and then pair the clinical history with findings from the genomic sequencing. The genomic sequencing can come from commercial Clinical Laboratory Improvement Amendment (CLIA)–certified sites or centers may have their own in-house genomic sequencing platform. After the patient’s genomic findings are summarized for the board, the medical oncologists discuss the relative efficacy/toxicity of potential treatment options based on published data and/or their own clinical expertise and recommend an appropriate treatment. The findings and the decisions of the board are documented and entered into the medical record for each of the individual patients that were discussed so all caregivers may review the recommendations.

CLINICAL CASE 1

Chief Complaint

Metastatic urothelial cancer

HPI

The patient is a 75-year-old man who developed gross hematuria over the period of a few weeks in August 2016. He had a cystoscopy that showed muscle-invasive, high-grade urothelial cancer, stage IIIA. He was surgical candidate and received neoadjuvant chemotherapy with cisplatin/gemcitabine followed by cystectomy with bladder reconstruction. Following recovery from surgery, he received 4 cycles of carboplatin and gemcitabine as planned adjuvant therapy. The patient was deemed to have no evidence of disease following completion of adjuvant therapy.

In September 2019, with routine follow-up the patient developed pleuritic chest pain and on a CT of the chest was found to have lymphadenopathy suggestive of potential metastatic disease. A biopsy was performed which confirmed the diagnosis of urothelial carcinoma. Given the patient’s age and prior exposure the platinum drugs he was deemed as “cisplatin ineligible” and was started on systemic treatment with atezolizumab.

The patient continued atezolizumab into summer 2020 when imaging confirmed a partial response. Unfortunately, in fall 2020, the patient was discovered to have new lesions in the chest on a CT scan. A lesion was biopsied and positive for urothelial carcinoma. The patient’s medical oncologist requests that genomic sequencing be performed by a commercial laboratory.

Past Medical History

Hypercholesterolemia

Congestive heart failure

Diverticulitis

Gastrointestinal reflux disease

Family History

Father, lung cancer diagnosed age 71, died age 73; mother, breast cancer, died at age 93. He has a paternal aunt and paternal grandmother who both were diagnosed with unspecified malignancies.

Social History

Retired prison employee. He drinks on average to 10 glasses of beer per week. He smoked a pack of cigarettes a day for 40 years; stopped smoking at age 55. He is married with two children.

Medications

Tamsulosin 0.4 mg PO daily

Furosemide 20 mg PO daily

Valsartan 160 mg PO twice daily

Gemfibrozil 600 mg PO daily

Omeprazole 20 mg PO daily

Acetaminophen 500 mg PO 6 times daily PRN pain

Allergies:

None

Review of Systems

No fever, chills, or sweats. No epistaxis or dysphagia. Reports no chest pain, shortness of breath, dyspnea, or cough. No nausea, vomiting, diarrhea, or constipation. He reports dysuria × 5 months with dribbling, nocturia 3 times per night, and incomplete voiding. He denies memory loss, diplopia, or neuropathy; he has had no falls recently. He reports a 15- to 20-year history of tinnitus.

Physical Exam
Gen

This is a pleasant, older gentleman who appears to be in moderate discomfort. Eastern Cooperative Oncology Group performance status 1.

VS

BP 122/71 mm Hg, Pulse 70 bpm, Respiratory Rate 20, Temp 37.9° C; Weight 89.5 kg, Height 5′7″

Skin

Warm and dry; no lesions or rashes

HEENT

Sclera are anicteric. Pupils equal, round, and reactive to light and accommodation; extraocular motion intact. Tympanic membranes are within normal limits bilaterally.

Neck/Lymph Nodes

No cervical or supraclavicular adenopathy

Lungs/Thorax

Lungs are clear in all fields. Respirations are even and unlabored.

CV

Normal rate and rhythm; S₁, S₂ normal; no murmurs, gallops, or rubs

Abd

No hepatosplenomegaly

Genit/Rect

No inguinal hernia on examination, otherwise WNL

Extremities

There is tenderness in lumbar area. 1+ ankle and pedal edema is present. Pedal pulses are 2+ bilaterally.

Neuro

CN II–XII grossly normal. Cerebellar function remains intact.

Results of Genomic Sequencing

Microsatellite stable

Tumor Mutation Burden (TMB) – 12 (elevated)

TERT promoter – 124C>T

TP53

ERBB3 mutation (exon 7 p.G284R)

Assessment

A 75-year-old man with newly progressive urothelial carcinoma. Potential treatment options are being considered by his primary medical oncologist who is looking to the results of genomic sequencing to guide further therapy.

What information is considered actionable based on the genomic findings?

The presence of the elevated TMB and the ERBB3 mutations are actionable. The elevated TMB suggests that the patient would be more likely to respond to immune checkpoint inhibitors such as atezolizumab, which the patient had been receiving.²¹ However, he has progressed following almost a year of treatment. The ERBB3 finding is potentially actionable; however, no therapy directed at ERBB3 in bladder cancer is currently approved by the U.S. Food and Drug Administration (FDA). The other identified mutations — TERT, a mutation involving a gene that determines telomere length; TP53, a tumor suppressor gene; and microsatellite stability – do not confer enhanced sensitivity to immune checkpoint inhibitors in the way tumor microsatellite instability does, making these mutations not actionable.

By way of background, the ERBB family of receptors includes epidermal growth factor receptor (EGFR, also known as HER1), HER2, ERBB3, and ERBB4. These are transmembrane receptors that each induce tyrosine kinase activity after binding by a ligand.²² Once bound, the receptor heterodimerizes the receptors and induces downstream cell signaling pathways that lead to oncogenic growth. ERBB3 is significantly less potent in inducing tyrosine kinase activity; it has to heterodimerize with other ERBB family members to promote downstream tyrosine kinase activity. Heterodimerization prompts the activation of prominent cell signaling pathways such as MAPK, PIK3CA/AKT/MTOR, SRC, and STAT pathways, all of which are known to be drivers of cancer cell growth. Colon, esophageal, gastric, endometrial, and bladder cancers are most commonly found to have ERBB3 aberrations, occurring in 1% to 4% of cases.^23,24

What potential treatment options could be considered for this patient?

An FDA-approved, third-line agent for bladder cancer, enfortumab vedotin-ejfv, is a monoclonal antibody drug conjugate directed at nectin-4, which is expressed on bladder tumor cells. Prominent toxicities associated with enfortumab vedotin-ejfv include hyperglycemia, ocular disorders such as blurred vision and keratitis, peripheral neuropathy, and skin toxicity. In patients who have experienced neuropathy related to prior exposure to platinum drugs, an oncologist may opt for a different treatment option.

Afatinib, approved by FDA in 2013 for EGFR-positive non-small cell lung cancer, is a tyrosine kinase inhibitor of the ERBB family. Highlights for the prescribing information of this agent can be found in Table 1.²⁵ A phase 2 trial of afatinib was conducted in patients who had urothelial carcinoma with genomic alterations in EGFR, HER2, ERBB3, and ERBB4; participants had progressive disease despite prior treatment with a platinum-containing regimen.²⁶ The trial enrolled 23 patients, 3 of whom had a documented ERBB3 mutation. When the drug was discontinued because of reduced ejection fraction, each of these 3 patients had a progression-free survival (PFS) for at least 6 months, with the longest being 10.3 months. Given these clinical data demonstrating clinical activity with afatinib in patients with ERBB3 aberrations, it is reasonable to consider afatinib for this patient.

If this patient was unable to obtain afatinib for coverage reasons, another reasonable consideration would be to evaluate the availability of clinical trials for patients with ERBB3 mutations. Table 2 provides a listing of open clinical trials in the United States with agents with activity directed at ERBB3 mutations as of fall 2020.²⁷ Eligibility criteria issues or travel issues may preclude patients from enrolling in trials withing the needed time period. In this case, the clinicaltrials.gov website can be searched again using updated study criteria if the patient progresses following salvage chemotherapy.²⁸ Also, for patients who might not meet the strict clinical trial entry criteria, the manufacturer can be contacted about the possibility of compassionate use of the investigational agent.

CLINICAL CASE 2

Chief Complaint

Metastatic triple negative breast cancer (TNBC)

HPI

The patient is a 50-year-old woman whose history dates back to a diagnosis of stage II, triple-negative, right-sided breast cancer in summer 2003. She underwent neoadjuvant chemotherapy with doxorubicin and cyclophosphamide followed by paclitaxel and then right mastectomy. She developed a recurrence in the right axilla in 2006, which was positive for TNBC on biopsy. She received salvage chemotherapy with docetaxel and gemcitabine x 5 cycles, which was stopped due to myelosuppression and changed to capecitabine. Shortly thereafter, she had an axillary lymph node dissection; pathology indicated a complete response, and the patient was considered to have no evidence of disease at that point.

In summer 2017, the patient developed hilar lymphadenopathy, which was reported as TNBC on biopsy. At this time, she was treated with single-agent carboplatin, which was continued until she developed progression in her paratracheal lymph nodes in June 2019; biopsy indicated TNBC. Her therapy was changed to eribulin, which has been continued to the present. A follow-up chest CT scan showed an interval progression in her paratracheal lymph nodes.

PMH

Meniscus tear during high school sports with no surgical intervention

Hypertension

Depression

Duodenal Ulcer

FH

Mother diagnosed with breast cancer at age 70, treated with surgery, chemotherapy, and radiation. She subsequently passed away due to a stroke. No other significant cancer history is noted.

SH

Noncontributory

Endocrine History

Menarche age 12; menopause age 48; first child age 22; G₁P₂A₀. Last Pap smear at age 45.

Meds

Omeprazole 20 mg PO once daily

Paroxetine 20 mg PO once daily

Hydrochlorothiazide 25 mg PO once daily

Zolpidem CR 12.5 mg PO at bedtime PRN sleep

Oxycodone/acetaminophen 5/325 mg, 1 to 2 tablets PO every 6 hours PRN pain

Prochlorperazine 10 mg PO every 6 hours prn nausea

All

NKDA

ROS

Negative except for complaints noted above

Physical Examination
Gen

Awake, alert, in NAD

VS

BP 123/82 mm Hg, Pulse 72 bpm, Respiratory Rate 14, Temp 37.7° C; Weight 66 kg, Height 5′4″

HEENT

NC/AT; Pupils equal, round and reactive to light and accommodation; extraocular motion intact; ear, nose, and throat are clear

Neck/Lymph Nodes

Supple. No thyromegaly or masses. No supraclavicular or infraclavicular adenopathy. Subtle lymphadenopathy surrounding the trachea.

Breasts

Unchanged from clinic visit; mastectomy scar well healed

Lungs

CTA and percussion

CV

RRR; no murmurs, rubs, or gallops

Abd

Soft, nontender/not distended, normoactive bowel sounds. No appreciable hepatosplenomegaly.

Ext

No CCE

Neuro

No deficits noted

Chest X-ray films

Lungs are clear

Genomic Sequencing

PIK3CA (Q1408*)

TP53 (R110P)

What information is would be considered actionable based on the genomic findings?

The presence of the phosphatidylinositol-3-kinase (PIK3CA) mutations is actionable. The FDA-approved agent alpelisib is a tyrosine kinase inhibitor directed at PIK3CA-mutated breast cancer.²⁹ However, this agent is approved only for patients with ER-positive disease; as such, it is licensed to be co-administered with fulvestrant. Information on alpelisib can be found in Table 3. As with first case, the TP53 mutation is not considered to be actionable.

By way of background, PIK3CA is the catalytic subunit of phosphatidylinositol-3-kinase, which is encoded by the PIK3CA gene, one of the most commonly mutated genes in cancer.⁴ PIK3CA activates a number of signaling cascades, including the AKT-mTOR pathway, an oncogenic promoter of cell survival and cell proliferation. Clinical trial data with agents aimed at the PIK3CA-AKT-mTOR (mammalian target of rapamycin) oncogenic pathway have had mixed success to date. The BELLE-4 trial with the investigational agent buparlisib did not improve PFS when added to paclitaxel in patients with advanced breast cancer.³⁰ For the 25% of the population with TNBC, buparlisib produced an approximately 4-month shorter PFS compared with single-agent paclitaxel. At this time, any therapy directed at PIK3CA mutations in TNBC should be evaluated only within the context of a clinical trial.

What potential treatment options could be considered for this patient?

Sacituzumab govitecan-hziy is a newly approved agent for patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease. General information about this agent is in Table 4.³¹ This agent is a novel monoclonal antibody drug conjugate that targets Trop-2, a 46-kD glycoprotein that is overexpressed in many epithelial cancers relative to normal tissue, including breast cancer.³²

The toxic payload for sacituzumab govitecan-hziy is SN-38, the active metabolite of irinotecan. SN-38 is a topoisomerase I inhibitor that produces apoptosis by inducing double-stranded DNA breaks.³³ The sacituzumab govitecan-hziy first binds to the Trop-2 cell surface antigen. The drug–antigen complex is internalized into the breast cancer cell, where SN-38 is released from the cleavable linker in the intracellular tumor microenvironment, resulting in death of the drug-infiltrated tumor cells and, following extracellular release of SN-38, to the adjacent tumor cells.^34,35 Other Trop-2 inhibitors, including SKB264 and DS-1062a, are in development for the treatment of different tumor types.²⁶

Approximately 20% of patients with breast cancer have TNBC, which characteristically has an aggressive disease course; the median overall survival (OS) is approximately 1 year from diagnosis of metastatic disease. The initial clinical data with sacituzumab govitecan-hziy in TNBC came from a phase 1/2 trial that evaluated the now-approved dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle in patients who had a median number of 5 lines of prior treatment for TNBC, which was given without regard for staining for Trop-2 overexpression.³⁶ During a median follow-up of 16.6 months among the 69 patients enrolled, the median number of doses administered per patient was 14, and 41% of participants developed a grade III or greater adverse event, the most common of which was neutropenia. Granulocyte colony-stimulating factor support was allowed during the trial. Other grade III or greater toxicities included leukopenia, anemia, diarrhea, hyperphosphatemia, vomiting, and thrombocytopenia. Regarding efficacy, 30% of patients achieved an objective response, and 2 patients achieved a complete response (CR).The median PFS was 6 months, median OS was 16.6 months, and 3 patients retained durable responses for 20 months. Trop-2 staining was obtained in 48 of the 69 patients; 42 patients had moderate (2+) to strong (3+) results, with the majority of patients expressing Trop-2 in more than 50% of tumor cells; all responders had moderate-to-strong Trop-2 expression.

Updated results were reported for a full cohort of 108 patients who had a shorter median duration of follow-up of 9.7 months and were less heavily pretreated than the initial cohort (median of 3 prior therapies).³⁷ Notable updates from the initial cohort was that a total of 3 patients achieved a CR, the duration of response was 7.7 months, and 11 patients exceeded a treatment duration of 12 months (median 5.1 months), with the longest approaching 36 months. The 12-month PFS was 42% and the median OS was 13 months.

The results of this trial have led to the development of a confirmatory phase 3 trial. It is comparing sacituzumab govitecan-hziy with physician’s choice of single-agent salvage chemotherapy using capecitabine, gemcitabine, vinorelbine, or eribulin in patients with metastatic-relapsed, refractory TNBC treated with at least 2 prior lines of chemotherapy.³⁸ Further development of sacituzumab govitecan-hziy is continuing in other tumor types, such as small cell lung cancer and non-small cell lung cancer.^39,40

PHARMACISTS’ ROLE IN IMPROVING OUTCOMES

A pharmacist on a precision medicine team plays an important and dynamic role. Activities include medication management of the patient’s anticancer regimen, medication counseling, symptom management, tumor board membership, assistance with drug procurement, policy and drug utilization guideline development, and support of genome-focused clinical trials.⁴¹ While institutions have subtle differences in responsibilities of pharmacy team members, the majority of programs have the pharmacist who work in precision genomics focus on genome analysis, crafting recommendations for drug therapy through participation in tumor board, evaluating patients for potential clinical trial involvement based on genomic findings, educating patients during follow-up clinic appointments on genomic results and potential treatments, and assisting with drug procurement. At the larger academic cancer centers, the precision genomics pharmacist collaborates with the pharmacists in the specialty pharmacy on off-label drug procurement.

Drug procurement can be a complicated endeavor for patients who receive recommendations for treatment of their cancer from a precision genomics program.⁴² Most often, the recommendations from MTBs are for either an off-label use of a commercially available anticancer agent or participation in a clinical trial that may or may not be available through local providers. For patients who receive a recommendation for an off-label use of an anticancer drug, navigating insurance approval is cumbersome. In most cases, the insurance company initially deny the authorization for payment for off-label use of the recommended drug. A precision genomics pharmacist supports the appeals process by submitting a letter of medical necessity documenting the patient’s treatment history and the deliberations of the MTB. The appeal may lead to either a peer-to-peer discussion, sometimes involving the pharmacist (at the discretion of the treating oncologist), or an outright denial. If the patient receives a final denial from the payer, another option is to request assistance from the manufacturer or investigate the availability of a compassionate-use protocol for the drug; the pharmacist is well suited to assist with these requests.

Another area of focus for a precision genomics pharmacist is managing interactions of oncolytic agents with other drugs or foods. Many oral anticancer agents have such interactions, and these require ongoing analysis and monitoring, especially when they involve CYP3A4-mediated metabolism.⁴³ Given the high number of drugs routinely used in patients undergoing cancer treatment — including antibacterial drugs, antifungal agents, and antihypertensives — the risk of drug–drug interactions looms large. The oncology pharmacist practicing in precision medicine maintains a primary role in mitigating the potential toxicity risk of these agents used concurrently. Further, minimizing the impact of potentially hepatotoxic and nephrotoxic drugs is crucial in managing this group of patients, as they often have advanced disease and may have end-organ compromise from anticancer drugs in prior lines of treatment.

An often overlooked but important practical matter in precision medicine is the potential need for an additional biopsy to obtain tumor tissue for genomic sequencing. With diagnoses of relapsed/refractory cancer, patients often have medical comorbidities as a consequence of their advancing malignancies and/or prior treatment. A common complication among this patient group is thromboembolism, which requires anticoagulation. A precision medicine pharmacist is often called upon to make recommendation for bridging or holding anticoagulant therapy around a biopsy procedure. Pharmacists should consult comprehensive recommendations when modifying anticoagulant therapy in such situations.^{44, 45}

The institutions that have established MTBs typically have a robust pharmacy training program for residents and students. Designing specialized clinical rotations for doctor of pharmacy students, postgraduate year 1 (PGY1) residents and PGY2 oncology residents provide exposure to young practitioners to the evolving technology of sequencing platforms, the analytic process of interpreting genomic sequencing results, and the approach to providing recommendations for treatment options to patients.⁴⁶ Further, PGY1 and PGY2 residents have ample opportunity to become involved in research projects that are suitable for presentation at their final residency research conference.

Precision genomics pharmacists can support such research efforts by encouraging PGY1/PGY2 residency projects in this practice area. First, pharmacists can serve as primary investigators or coinvestigators for drug trials. Further, pharmacists can collaborate with precision genomics team in submitting large grant proposals for clinical trial with correlative science work to further understand drug response based on genomic predictors.⁴⁷ Engagement of precision genomics pharmacists can extend to roles with the NCI cooperative group structure or more local oncology cooperative groups to facilitate development of clinical trials that are focused on genomics.

CONCLUSION

The age of precision medicine in oncology is now well established in standard clinical oncology practice. The American Society of Health-System Pharmacists (ASHP) has validated this practice by issuing a consensus statement that explicitly describes adjustment of drug regimens based on genetic factors as an essential activity of pharmacist-provided direct patient care.⁴⁸ ASHP cites institutions using genome-informed drug decision making to support clinical decision support in electronic medical records, inform institutional criteria for drug prescribing, and create new teaching modules for pharmacy residency training and didactic course work.

Precision genomics pharmacy practitioners are in the forefront of this paradigm shift on the strength of sound clinical drug utilization knowledge, understanding of the pharmacodynamics and pharmacokinetics of traditional and targeted anticancer agents, and understanding of the application of genomic sequencing findings to facilitate drug choice based on the molecular pathology traits of individual patients.

REFERENCES

1. Prescribing information. Novartis. Updated January 2012. Accessed September 2, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021588s035lbl.pdf
2. Hochhaus, A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–927.
3. Evans WE, Johnson JA. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu Rev Genomics Human Genet. 2001;2:9–39.
4. Domchek SM, Mardis E, Carlisle JW, Owonikoko TK. Integrating genetic and genomic testing into oncology practice. ASCO Educ Book. 2020;40:e259–e263.
5. Alexander TB, Gu Z, Iacobucci I, et al. The genetic basis and cell of origin of mixed phenotype acute leukemia. 2018;562:373–379.
6. Aquliante CL, Zineh I, Beitelshees AL, Langaee T. Common laboratory methods in pharmacogenomics studies. Am J Health Syst Pharm. 2006;63:2101–2110.
7. Berger MF, Mardis ER. The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 2018;15:353–365.
8. Human Genome Sequencing Consortium I; International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. 2004;431:931–945.
9. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. 2013;339:1546–1558.
10. Levy SE, Myers RM. Advancements in next-generation sequencing. Annu Rev Genomics Hem Genet. 2016;17:95–115.
11. Slatko BE, Gardner AF, Ausubel FM. Overview of next generation sequencing technologies. Curr Protoc Mol Biol. 2018;122:e59.
12. Hansen MC, Haferlach T, Nyvold CG. A decade of whole exome sequencing in haematology. Br J Haematol. 2020;188:367–832.
13. Relling MV, Evans WE. Pharmacogenomics in the clinic. 2015;526:343–350.
14. Khan SS, Chen AP, Takebe N. Impact of NCI-MATCH: a nationwide oncology precision medicine trial. Expert Rev Precis Med Drug Dev. 2019;4:251–258.
15. Mangat PK, Halabi S, Bruinooge SS, et al. Rationale and design of the Targeted Agent and Profiling Utilization Registry (TAPUR) study. JCO Precis Oncol. 2018 Jul 11. doi: 10.1200/PO.18.00122.
16. Van der Velden DL, van Herpen CML, van Laarhoven HWM, et al. Molecular tumor boards: current practice and future needs. Ann Oncol. 2017;28:3070–3075.
17. Rao S, Pitel B, Wagner AH, et al. Collaborative, multidisciplinary evaluation of cancer variants through virtual molecular tumor boards informs local clinical practices. J Clin Cancer Inform. 2020;4:602-613.
18. Levit LA, Kim ES, McAneny BL, et al. Implementing precision medicine in community–based oncology program: three models. J Oncol Pract. 2019;15:325–329.
19. Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathology. J Mol Diagn. 2017;19:4–23.
20. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
21. Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–206.
22. Memorial Sloan Kettering Cancer Center. ERBB family mutations. OncoKB.org. Accessed September 30, 2020. https://www.oncokb.org/gene/ERBB3
23. Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12:45–62.
24. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer from a prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–713.
25. Prescribing information. Boehringer-Ingelheim. Updated January 2018. Accessed September 30, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf
26. S. National Library of Medicine. ClinicalTrials.gov. Accessed September 30, 2020. www.clinicaltrials.gov
27. Choudry NJ, Campanile A, Antic T, et al. Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. J Clin Oncol. 2016;34:2165–2171.
28. Prescribing information. Novartis. Updated May 2019. Updated January 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf. Accessed September 16, 2020.
29. Memorial Sloan Kettering Cancer Center. ERBB family mutations. OncoKB.org. Accessed October 3, 2020. https://www.oncokb.org/gene/PIK3CA
30. Pascual J, Turner NC. Targeting the PI3 kinase pathway in triple-negative breast cancer. Ann Oncol. 2019;30:1051–1060.
31. Prescribing information. Immunomedics. Updated April 2020. Accessed August 10, 2020. https://trodelvy.com/pdf/PrescribingInformation.pdf
32. Goldenberg DM, Stein RS, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP–2) as a novel cancer target. 2018;9:28989-29006.
33. Sahota S, Vahdat LT. Sacituzumab govitecan: an antibody-drug conjugate. Expert Opin Biol Ther. 2017;17:1027-1031.
34. Goldenberg DM, Sharkey RM. Sacituzumab govitecan, a novel third generation, antibody-drug conjugate (ADC) for cancer therapy. Expert Opin Biol Ther. 2020;20:871–885.
35. Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). 2015;6:22496–22512.
36. Bardia A, Mayer IA, Diamond JR, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol. 2017;35:2141–2148.
37. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380:741–751.
38. The ASCENT Phase III trial comparing sacituzumab govitecan-hziy to chemotherapy in metastatic TNBC. Accessed October 2, 2020. https://www.clinicaltrials.gov/ct2/results?cond=&term=02574455&cntry=&state=&city=&dist
39. Gray JE, Heist RS, Starodub AN, et al. Therapy of small cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2, sacituzumab govitecan. Clin Cancer Res. 2017;23:5711–5719.
40. Heist RS, Guarino MJ, Masters G, et al. Therapy of advanced non-small cell lung cancer with an SN-38 anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol. 2017;35:2790–2797.
41. Walko C, Kiel PJ, Kolesar J. Precision medicine in oncology: new practice models and roles for oncology pharmacists. Am J Health Syst Pharm. 2016;73:1935–1942.
42. Raheem F, Kim P, Grove M, Kiel PJ. Precision genomic practice in oncology: pharmacist role and experience in an ambulatory clinic. 2020;8:32.
43. Indiana University of School of Medicine. Drug Interactions Flockhart Table. Accessed February 14, 2020. https://drug-interactions.medicine.iu.edu/MainTable.aspx
44. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy. 2012;141(2)(suppl):e326s–e350s.
45. Burnett AE, Mahan CE, Vazquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206–232.
46. Weitzel KW, Aquilante CL, Johnson S, Kisor DF, Empey PE. Educational strategies to enable expansion of pharmacogenomics-based care. Am J Health Syst Pharm. 2016;73:1986–1998.
47. Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. 2015;526:361–370.
48. Valgus J, Weitzel KW, Peterson JF, Crona DJ, Formea CM. Current practices in the delivery of pharmacogenomics: impact of the recommendations of the Pharmacy Practice Model Summit. Am J Health Syst Pharm. 2019;76;521–529.