Evolution of Precision Oncology, Personalized Medicine, and Molecular Tumor Boards

Introduction

Precision oncology is the concept of providing treatment based on individual patient’s tumor mutation profiles. In recent years, new therapeutic options are regularly being approved for specific cancer patient populations based on corresponding gene alterations and biomarkers.¹ Although biomarker-driven approaches have been developed mainly for patients with advanced cancer, the rapid development of these therapeutics also allows the incorporation of personalized medicine into the adjuvant/neoadjuvant settings along with curative intent surgery and/or radiotherapy. This integration suggests the importance of early molecular profiling testing to determine the best therapy through multidisciplinary discussions for patients with both early and advanced-stage cancers.²

Therapeutic options for patients with advanced cancer were historically limited to cytotoxic chemotherapy until the discovery of “targetable” mutations, which revolutionized the cancer treatment landscape. Early examples of these molecular targeted therapies included imatinib for BCR-ABL chronic myeloid leukemia and erlotinib for epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma.^3–5 Since the development of these agents, the advent of next-generation sequencing (NGS) has allowed clinicians to rapidly identify targetable molecular alterations with novel drugs that may provide better clinical outcomes than classical cytotoxic chemotherapy.^{6, 7} These alterations can be observed across cancer types and molecular targeted therapies may have clinical activity across tumor types.^{8, 9} Furthermore, recent developments in immunotherapy, including immune checkpoint inhibitors (ICIs), have dramatically changed the paradigm of cancer treatment by providing durable responses in some cancer patients.¹⁰ Several factors such as high programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) have been associated with prolonged survival and could potentially be used as biomarkers to select patients before initiating ICIs.^{11, 12} It is through our increased understanding of tumor biology that treatment is evolving.

This chapter summarizes the development of precision oncology, the role of molecular tumor boards (MTB), and future directions of personalized medicine for patients with cancer including those who are candidates for surgical intervention.

Discussion

History

The evolution of precision oncology dates back to the late 1990s, when imatinib was found to be effective in chronic myeloid leukemia (CML) harboring BCR-ABL rearrangement, leading to approval by the U.S. Food and Drug Administration (FDA) in 2001.³ Along with the development of techniques such as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) which allowed rapid detection of targetable alterations, several molecular targeted therapies were subsequently developed. One of the first example of precision medicine for solid tumors was use of a tyrosine kinase inhibitor (TKI), such as erlotinib and gefitinib, for patients with non-small cell lung carcinoma (NSCLC) harboring an EGFR mutation. Gefitinib was initially shown to be effective for NSCLC patients but subgroup analysis suggested that its efficacy was driven by EGFR-mutant population, which was subsequently confirmed in a clinical trial limited to patients with an EGFR mutation.^{5, 13, 14} Erlotinib was also developed and firstly approved specifically for patients with EGFR-mutant NSCLC in 2013.¹⁵ This small molecule inhibitor became the focus of attention as it inhibits a specific alteration rendering more efficacy with potentially less toxicity than traditional cytotoxic chemotherapy. Thus, its application was incorporated into the standard of care in patients with malignancy.^{6, 7}

The initial development of molecular-targeted agents was achieved by dividing a specific cancer type into subtypes according to genomic mutation patterns such as EGFR, anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS1) inhibitors for NSCLC.¹⁶ However, as different types of cancer can share the same genomic alteration, the tumor-agnostic approach has been explored to broaden the application of targeted therapies. In 2019, entrectinib, an neurotrophic tyrosine receptor kinase (NTRK) inhibitor, was approved by the FDA for solid tumors with NTRK fusion regardless of cancer type after demonstrating its efficacy (durable overall response rate of 57%). Similarly, pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, was approved by the FDA in patients with DNA mismatch repair-deficiency (dMMR) or microsatellite instability-high (MSI-H) tumors in 2017, and in patients high TMB tumors in 2020, respectively.^18–20 These strategies have highlighted the importance of performing NGS to expand treatment options without losing the chance of a potentially long-lasting therapeutic opportunity. As personalized medicine evolves, the treatment landscape becomes more complicated because each cancer possesses a different genetic profile. Currently, multiple agents are approved for specific alterations in one tumor type and for the same alteration across cancer types. For example, there are five FDA-approved ALK inhibitors for NSCLC, three tumor-agnostic indications for the use of pembrolizumab in solid tumors, and two NTRK inhibitors for solid tumors harboring NTRK fusions.^18–22 Therefore, discussions in a multidisciplinary fashion at a Molecular Tumor Board (MTB) play a more important role in determining the best treatment for each patient by considering their performance status and comorbidities, the side effect profile of the matched agents, and access to clinical trials.²³

Precision Oncology in Clinic

Historically, precision oncology has been delivered primarily to patients with advanced malignancies after progression on multiple lines of chemotherapy. To explore further therapeutic opportunities such as molecular targeted therapy that are not approved for a specific cancer type and enrollment in clinical trials, genomic profile tests can be performed through NGS. Clinicians need to explain the concept of testing to obtain a genomic profile from tumor tissue or liquid samples, including the benefits and risks of testing to the patients (Table 1). In particular, physicians need to explain the potential risk of detecting a germline mutation, as this would affect the medical care for patient’s relatives, such as an increased risk of developing cancer in siblings and children.²³ In this case, consultation for genetic counseling may be necessary. Additionally, the detection rate of effective treatments for a cancer can be relatively low (~5-20%) at present, and patients need to understand what the next process looks like if no therapeutic options are available after performing the genomic profiling test.² Insufficient amount of tissues or remote tissue samples also make it difficult to perform NGS, and in this case, additional biopsy might be needed. Liquid biopsy is another option that may provide up-to-date genomic information in a non-invasive way.^{24, 25}

Table 1.

Risk and benefit upon performing genetic profiling testing for precision medicine.

	Benefits	Risks
Therapeutic options	Finding a treatment option available on the market. Example: EGFR mutation for EGFR TKI.	Treatment corresponding to a detected alteration is not available on the market. Example: KRAS G12V mutation (only KRAS G12C inhibitors are available).
Predictive marker	Detecting a predictive biomarker for a specific therapy. Example: High tumor mutational burden (TMB) for immune checkpoint inhibitors.	Can potentially find a factor that negatively predicts the therapeutic efficacy. Example: Low tumor mutational burden which could potentially decrease the efficacy of immune checkpoint inhibitors.
Clinical trials	Finding actionable alterations for which many clinical trials are available.	Mutations whose molecular structures make them undruggable. Limited options of clinical trials.
Genetic information	Detection of somatic mutations only. Counseling of relatives can be omitted in this case.	Possibility of detecting germline mutations that predispose to the risk of developing cancer in relatives. Genetic counseling may be necessary.

Abbreviations: EGFR, Epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog; TKI, tyrosine kinase inhibitor.

Molecular Tumor Board (MTB)

Once a genomic profiling is obtained from tissues and/or liquid samples, the result and potential treatment options need to be discussed in a multidisciplinary manner to provide the best and most personalized care with the potential for maximum treatment benefit, taking into account factors such as comorbidities and access to care. The MTB plays an integral role in clinical decision making by facilitating discussions with expertise in medical oncology, surgical oncology, bioinformatics, clinical genomics, genetic counseling, and radiation oncology (Figure 1).²³ Genomic data can provide potential treatment options for targetable alterations and biomarkers to predict the efficacy of available therapies. Through multidisciplinary discussions by obtaining perspectives from each specialist, the MTB may suggest consideration of experimental drugs, enrollment in clinical trials, and use of approved agents, based on the available evidence. On top of the genomic profile, information on clinical status such as performance status, active medical issues, access to health care such as whether patients need to be referred to another institution for clinical trials will be discussed.

Figure 1.

Concept of precision medicine and role of molecular tumor board.

The flowchart to perform precision medicine from specimen sampling, analysis, discussion at molecular tumor board, to treatment suggestions. Created with BioRender.com.

Abbreviation: TMB, Tumor mutational burden.

The role of MTBs is critical to improve survival outcomes for patients with advanced cancers. Patients with genomic alterations for which targeted therapies are available are more likely to benefit from “matched” treatments more than those with physician’s choice treatment mostly due to the unavailability of agents for their alterations. For example, if patients are matched with agents recommended by the MTB, clinical outcomes such as objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) may be improved more than those treated with physician’s choice treatment.²⁶ These approaches have been implemented for patients with advanced malignancies, particularly those with limited treatment options after disease progression on several lines of treatment. However, precision medicine approaches are now rapidly being incorporated into earlier lines of therapy for patients with advanced disease, as well as the curative setting for patients treated with neoadjuvant or adjuvant therapy. Dating back to the 1970s, the hormonal therapy, tamoxifen, was shown to delay recurrence in early breast cancer. Tamoxifen and aromatase inhibitors have been used for hormone receptor-positive breast cancer.²⁷ Also in breast cancer, HER2 inhibitors such as trastuzumab and pertuzumab showed survival benefits when used as neoadjuvant and/or adjuvant therapy in those with ERBB2 amplified tumors.^28–30 Immunotherapy such as ICIs has also been shown to be effective when used perioperatively by improving relapse-free survival and OS in patients with certain cancers.^31–36 Therefore, MTBs are becoming increasingly valuable for input and discussion not only from experts providing systemic therapy, but also from experts providing curative treatment such as surgery and radiotherapy.

Clinical Outcomes by Implementing Precision Medicine and Molecular Tumor Board

Traditionally, clinical trials evaluated patients with a specific cancer, and most did not select patients based on biomarkers that could potentially predict the efficacy of corresponding agents. The era of precision medicine has required novel clinical trial designs that make personalized therapy evaluable and feasible (Table 2). Several clinical trial designs have been developed to evaluate the feasibility and efficacy of MTBs and to assess agents selected based on genomic profile information as summarized in a previous review article.³⁷ Compared with these traditional clinical, precision medicine requires the evaluation of genomic profiles and the administration of agents matched with genomic alterations. Trials with master protocols allow assessment of more than one drug or one tumor within a single clinical trial.³⁸ Basket and umbrella trials are the first generation of clinical trials implementing precision medicine. Basket trials evaluate agents against a specific genetic alteration regardless of cancer type, leading to the successful development of pembrolizumab, NTRK inhibitors, BRAF and MEK inhibitors for BRAF V600E mutations, and RET inhibitors for RET mutation in a tumor-agnostic manner (Figure 2).^39–41 In contrast, umbrella trials evaluate multiple molecular alterations within a single cancer type to address heterogeneity within patients with a specific tumor type.³⁷ Umbrella trials are advantageous when evaluating common cancers with multiple alterations such as lung cancer and breast cancer.³⁷ When master protocols evaluate multiple hypotheses in one protocol, they are referred to as platform trials. The IMPACT1 trial, a platform trial, demonstrated the feasibility of the efficacy of precision medicine by showing better survival in patients with matched agents than those without matched therapies.^{42, 43} Several platform trials are ongoing such as IMPACT2 and NCI-MATCH across tumor types to evaluate agents matched to unique genomic alterations.^{37, 44} In particular, the NCI-MATCH trial comprises 40 treatment arms to evaluate agents “matched” to alterations of each patient, and demonstrated its feasibility of patient enrollment and performing NGS. Clinical benefit varied across targeted agents but approximately 38% of enrolled patients were found to have potential molecular targets and 18% of patients received matched agents.^{45, 46}

Table 2.

Clinical trial and research design evaluating precision medicine that includes a molecular tumor board.

Design	Design detail	Pros	Cons	Study References
Master protocol
Basket trial	Tissue-agnostic, assessing agents targeting a common pan-cancer gene alteration.	Can broaden the indication of one agent to multiple tumor types.	Not all driver alterations are successfully targeted due to heterogeneity across tumor types.	TAPUR*82–84
Umbrella trial	Tumor histology-specific, assessing several agents in different genomic subsets.	Can address inter-patient heterogeneity of a specific tumor type.	Difficult to implement clinical trials for rare tumors. Hard to determine treatment arms when a patient has multiple actionable alterations.	TAPUR*82–84
Platform trial	Trial allowing assessment of several hypothesis in one protocol.	Can expand or delete treatment arms even when clinical trials are running. Can assess multiple biomarkers and targetable alterations in one clinical trial. Cost-effective.	Complicated clinical trial design. High burden on trial administration. Complexity of statistical analysis.	IMPACT142, 43 IMPACT285, 86 TAPUR*82–84
Newer generation
N-of-1 trial	Patient-centered trial evaluating individualized combination treatments. The degree of matching to therapy suggested by the molecular tumor board is assessed. Outcomes are compared among patients treated with low vs. high degree of molecular matching.	Can offer individualized combination treatment approaches for each enrolled patient by considering their molecular features.	Complexity of calculating the degree of matching. Difficult to generalize the trial outcomes to different populations. Patients are treated with customized combination therapies that are unique to each patient.	I-PREDICT48, 49
Others
Real-world data	Analyzing data obtained in electronic medical records and industrial patient data to address unmet needs in real world.	Can address unmet needs and clinical questions that arise in daily practice. Cost effective.	Patient and treatment selection possess a risk of bias as real-world data analysis is not a prospective clinical trial.	USCD-PREDICT (NCT02478931)26

^*Combination of Basket and umbrella trial.

Details of each trial listed and other trials not listed here are summarized in previous review articles.^{37, 87}

Figure 2.

Evolution of tumor-agnostic precision oncology in the United States.

Each column includes: (1) Agent name, (2) Targeted alterations, and (3) Targeted population. Created with BioRender.com.

Abbreviations:

BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; dMMR, DNA mismatch repair-deficiency; MEK, Mitogen-activated protein kinase kinase; MSI-H, Microsatellite instability-high; NTRK, Neurotrophic tyrosine receptor kinase; PD-1, Programmed cell death protein 1; RET, Rearranged during transfection.

The next generation of clinical trials implementing precision medicine includes N-of-1 trials.⁴⁷ In contrast to conventional clinical trials, N-of-1 trials focus on individualized therapy for patients with cancer. This design aims to evaluate the efficacy and safety at the level of an individual patient. Information gathered from N-of-1 trials may provide a tailored therapeutic strategy for individuals by addressing the inter-patient heterogeneity of their cancer.^{2, 47} The Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) trial was the first prospective trial to use the N-of-1 trial design to evaluate personalized treatment suggested by the MTB for patients with advanced cancer. Therapy was suggested based on evaluated biomarkers from tissue NGS, circulating tumor DNA (ctDNA), and immune markers including MSI status, TMB, and PD-L1 expression. Treatment efficacy was assessed by calculating a “matching score” representing the degree of matched therapies. For example, if a patient had 4 alterations and was given therapy that targets 1 alteration, the matching score was 1/4 (= 25% [low]). In contrast, if a patient had 4 alterations and was given therapy that targets 3 alterations, a matching score was calculated as 3/4 (= 75% [high]). In this study, higher matching score (>50%) was associated with a statistically better DCR (defined as partial response or stable disease ≥ 6 months), as well as improved PFS and OS across tumor types when compared to patients who received therapies with a low matching score.^{26, 48–50} Overall, the I-PREDICT trial showed the feasibility and safety of N-of-1 trials, customizing personalized treatment approaches provided by the MTB.

The number of studies utilizing MTBs for delivering precision medicine is growing. A recent study by the University of California, San Diego investigated the utility of MTB showed that a higher matching score in patients with colorectal cancer was associated with longer PFS (HR, 0.41; 95% CI, 0.21-0.81; P = 0.01) with higher clinical benefit rates (41% vs. 18%, P = 0.058) than those treated with “unmatched” therapy. The authors concluded that MTB plays a vital role in treatment decision making and survival improvement in a specific cancer type.⁵¹ Because it is difficult for traditional clinical trials to ensure the feasibility of precision medicine, we anticipate that more clinical trials will implement trial designs such as N-of-1 trials. Clinicians involved in the care of patients with cancer need to understand the newer concept of these trials to develop new evidence for patient care through personalized medicine.

Perioperative Precision Oncology

Somatic alterations

Precision oncology through biomarker-based patient selection is now growing in the perioperative setting as neoadjuvant/adjuvant therapy (Table 3). Breast cancer was one of the first cancers to consider patient selection based on biological characteristics. Endocrine therapy such as tamoxifen and aromatase inhibitors are standard adjuvant therapy in hormone receptor-positive patients, and HER2-targeting agents such as trastuzumab and pertuzumab are now used as a neoadjuvant and adjuvant therapy in locally advanced disease with ERBB2 amplification.^{29, 30} Additionally, a CDK4/6 inhibitor, abemaciclib, has been shown to prolong relapse-free survival in hormone receptor-positive breast cancer with high risk features in the MonerchE trial, expanding further options in patients with breast cancer as a perioperative strategy.⁵² In lung cancer, the ADAURA trial showed survival improvement with osimertinib, an EGFR TKI, after definitive surgery with or without adjuvant chemotherapy, expanding further personalized options in other cancer types.⁵³

Table 3.

Examples of precision oncology in the perioperative setting

Cancer	Example	Population	Agents	References
Breast cancer	Adjuvant hormonal therapy	Hormone-receptor positive	Tamoxifen Aromatase inhibitors	27, 88
	Neoadjuvant/adjuvant HER2 inhibitors	ERBB2 amplification	Trastuzumab Pertuzumab Trastuzumab-emtansine (for residual disease)	29, 30, 89
	Adjuvant PARP inhibitors	BRCA1/2 mutations HRD	Olaparib	59
	Adjuvant CDK4/6 inhibitors	High-risk hormone-receptor positive	Abemaciclib	52
Colorectal cancer	Neoadjuvant immunotherapy	Mismatch repair-deficient rectal cancer	Dostarlimab*	90
Lung cancer	Adjuvant EGFR TKI	EGFR mutation	Osimertinib	53
Malignant melanoma	Adjuvant BRAF and MEK inhibitors	BRAF V600E or V600K mutations	Dabrafenib plus trametinib	91
Ovarian cancer	PARP inhibitors	BRCA1/2 mutations	Olaparib	92

^*Not FDA-approved.

Abbreviations:

BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; BRCA, BReast CAncer gene; CDK, Cyclin-dependent kinase; EGFR, Epidermal growth factor receptor; ERBB2, Erythroblastic oncogene B 2; HER2, Human epidermal growth factor receptor 2; HRD, Homologous recombination deficiency; MEK, Mitogen-activated protein kinase kinase; NSCLC, Non-small cell lung cancer; PARP, Poly-ADP ribose polymerase; TKI, Tyrosine kinase inhibitor.

Other than targeted therapy, ICIs are now being incorporated into the standard of care as either neoadjuvant or adjuvant therapy by showing improvement in relapse-free survival and OS in multiple cancer types.^{31–33, 35, 36} In this setting, an appropriate biomarker for patient selection has not yet been established, but PD-L1 expression may be a positive predictor for relapse-free survival based on subgroup analyses in these trials.^{32, 33, 36}

Germline alterations

In addition to a strategy targeting somatic mutation, patients with germline mutation also benefit from precision medicine. For example, poly-ADP ribose polymerase (PARP) inhibitors such as olaparib improve survival in patients with breast cancer harboring BRCA1/2 mutations.⁵⁴ Subsequently, the “maintenance” use of PARP inhibitors showed benefit by prolonging relapse-free survival in BRCA-mutant ovarian cancer.⁵⁵ Their use has also been expanded to other tumor types such as advanced pancreatic cancer and metastatic castration-resistant prostate cancer harboring BRCA mutations.^56–58 PARP inhibitors are also being used in the perioperative setting. Adjuvant use of olaparib for HER2-negative early breast cancer harboring BRCA1 or BRCA2 germline mutations with high-risk clinical features showed prolonged invasive disease-free survival (HR, 0.58, 99.5% CI, 0.46-0.74, P < 0.0001) and OS (HR, 0.68, 99.5% CI, 0.50-0.91, P < 0.0091) compared to placebo after neoadjuvant or adjuvant chemotherapy, leading to its FDA approval in 2022.^{59, 60} Thus, we anticipate an increase in the number of early-stage cancer cases requiring genomic profiling tests before or after surgery to guide appropriate perioperative therapy, including the use of PARP inhibitors. As they are now utilized in upfront therapy, all providers need to understand the long-term risks of PARP inhibitors such as a potential increase in the risk of treatment-related myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) as well as the incidental detection of germline mutations in their relatives resulting in an increase in risk of several cancer types.²³

The I-SPY 2 trial, implementing perioperative tailored approach, has a framework of an adaptive phase 2 clinical trial design evaluating neoadjuvant therapy for patients with high-risk breast cancer. The trial categories breast cancer into 10 subtypes according to hormone receptor and HER2 status, and 70-gene assay (MammaPrint) score. For randomization, Bayesian methods are used to achieve a higher probability of efficacy in the use of experimental drugs in addition to standard neoadjuvant chemotherapy.^{61, 62} This platform trial is ongoing to identify new agents combined with standard neoadjuvant chemotherapy and ideal strategies for each patients with early stage high-risk breast cancer.

Precision oncology is now rapidly becoming the standard of care even in the early stage setting as part of neoadjuvant/adjuvant therapy (Figure 3). Performing NGS and molecular profiling tests at the time of cancer diagnosis must be strongly considered to gain maximum therapeutic benefit. Details of treatment for each type of cancer are summarized and discussed in other chapters.

Figure 3.

Development of peri-operative precision oncology.

Each column includes: (1) Agent name, (2) Targeted alterations, and (3) Targeted population. Created with BioRender.com.

Abbreviations:

BRAF, V-Raf Murine Sarcoma Viral Oncogene Homolog B; BRCA, BReast CAncer gene; CDK, Cyclin-dependent kinase; EGFR, Epidermal growth factor receptor; HER2, Human epidermal growth factor receptor 2; MEK, Mitogen-activated protein kinase kinase; NSCLC, Non-small cell lung cancer; PARP, Poly-ADP ribose polymerase.

Challenges of Precision Medicine and Molecular Tumor Board

Expertise

Multidisciplinary discussion facilitates treatment consideration and selection at the MTB. However, availability of experts to conduct the MTB can be challenging, particularly in small institutions, rural areas, and developing countries.^{23, 63} Additionally, time constraints may be another issue as experts may not be available at the same time. In institutions with limited access to individual subspecialists, creating a tumor board team that works remotely both internally and externally can address this issue.⁶⁴ Further, education and lectures created by experienced institutions may also help each clinician improve their understanding of the interpretation of genomic test results, resulting in improved feasibility of MTBs in any institution with limited access to experts. Precision oncology using NGS and clinical trials have developed primarily in Western countries. Experts in these fields could facilitate the process of holding the MTB in other regions by working remotely, and the feasibility of a virtual MTB has been shown in several studies from Western countries.^{63, 65} Clinical trials assessing precision medicine are also being performed in Asian countries and expansion to other regions is expected in the near future.^66–68 Broadening the application of precision oncology in these areas would improve survival outcomes in patients with cancer worldwide by addressing racial and ethnic molecular differences.^{69, 70} Further global collaborations are needed to address these MTB feasibility issues.

Access to Clinical Trials

However, access to treatment can also be problematic even in larger clinical cancer centers. The MTB suggests tailored therapeutic option for each patient. Oftentimes, clinical trials are the only option that can be suggested as an experimental therapeutic option, which may not be available at their institution. Transferring from the original institution could be a burden for patients, and thus, smooth referral to the new clinical site where clinical trials are available is necessary for seamless care. There is a growing demand for collaboration through a clinical trial network to reduce patient burden and ensure access to clinical trials across the country.²³

Unanticipated Germline Findings

The challenging aspect of genetic testing for both clinicians and patients is the possibility of detecting germline genomic alterations. A pathogenic germline variant can be detected in approximately 4-12 % of patients using genomic profiling.^71–74 These findings can lead to prescribing treatments such as PARP inhibitors for BRCA1/2-mutant cancers and those with homologous recombination deficiency (HRD), but could also result in family members of these patients being at increased risk of developing cancer in the future due to specific germline mutations. Institutional support such as a genetic counselor must be established at centers where genetic profiling tests are performed. Clinicians should be aware of the psychological burden of detecting germline mutations in patients and their family members. The risk-benefit discussion by providing data such as the detection rate of treatable alterations and germline mutations needs to be carefully conducted with each patient undergoing genomic profiling.

Tumor heterogeneity and evolution

Traditional genomic profiling tests have “static” characteristics, in which tissue or liquid biopsies are collected and analyzed for clinically meaningful expression or actionable genetic alterations at a single time. Although some patients can gain useful information from genomic profiling for treatment decisions, it would be difficult for static analyses to account for tumor heterogeneity and evolution within each patient over time. Recently, the concept of “functional precision medicine” has been proposed, which is an approach based on exposing patient samples to existing or experimental drugs.⁷⁵ In the future, integrating the functional precision medicine approach would allow us to determine which drugs are more potent and effective for each patient. Challenges to functional precision medicine include techniques for handling patient tissues, unclear clinical associations between in vivo analysis and actual patient outcome, and the time from tissue collection, creation of specific models such as cell lines, organoids, and xenograft models, to drug testing.⁷⁶ There are ongoing clinical trials evaluating the feasibility and utility of functional precision medicine. The integration of traditional genomics-driven, “static” precision medicine and functional precision medicine would provide better rationale for combination treatments and facilitate better discussion in the MTB.⁷⁶

Perioperative Toxicity

In the perioperative setting, the toxicity of agents suggested by the MTB needs to be carefully considered because severe adverse events from targeted therapies or immunotherapy can delay surgery and affect quality of life in patients whose cancer is potentially curable (see article by Nishizaki and Eskander). To implement the personalized medicine in the early setting, future clinical trials incorporating MTB and precision oncology must assess the safety and the impact of toxicity on the outcome of definitive therapy to optimize outcomes.

Future Directions

Clinical trials evaluating precision oncology have demonstrated its feasibility and survival benefits across tumor types leading to the rapid expansion of tailored medicine for patients with solid tumors. Particularly, molecular targeted therapies and immunotherapy are being actively incorporated into neoadjuvant and adjuvant therapy with surgery, suggesting the need for the MTB in the perioperative setting to deliver the best personalized therapeutic strategy to increase the chances of cancer cure.

Current issues and challenges with molecular targeted therapy and ICIs are that the majority of patients receiving these agents eventually acquire resistance and show disease progression while receiving these treatments. Precision medicine trials showed feasibility of patient enrollment and sequencing, but have also shown that therapies targeting a single alteration do not provide significant benefit.⁴⁴ As cancer cells acquire some escape pathways after exposure to these agents, strategies to combine two or more agents have been proposed and evaluated to improve treatment outcomes in recent clinical trials.^{77, 78} The NCI-ComboMATCH was launched to search for ideal combination therapies based on evidence from preclinical studies.⁷⁹ Results from this type of clinical trials will provide useful information to guide treatment decisions at the MTB.

The development of antibody-drug conjugates (ADCs), bispecific antibodies, cellular therapy, and radionuclide therapy will also expand precision medicine. The use of ADCs for cancer treatment is growing dramatically. ADCs are composed of a cytotoxic payload, an antibody to target antigens expressed on tumor cells, and a linker to connect the payload and antibody. Examples of ADCs in oncology include enfortumab vedotin (payload: MMAE, target antigen: nectin-4), trastuzumab deruxtecan (payload: DXd, target antigen: HER2), and sacituzumab govitecan (payload: SN-38, target antigen: Trop-2). Since antigen expression patterns differ between tumor types, ADCs have been evaluated for specific tumor types. Recently, trastuzumab deruxtecan demonstrated a promising objective response rate (37.1% in the entire population; 61.3% in patients with IHC 3+ expression) for HER2 overexpressing tumors in the pan-cancer setting (NCT04482309, DESTINY-PanTumor02), suggesting the utility of ADCs as a tumor-agnostic approach.⁸⁰ Additionally, bispecific antibodies and cellular therapy targeting specific tumor-associated antigens on cancer cells also implement the concept of personalized medicine. Radionuclide therapy such as Lutetium-177–PSMA-617 has also been shown to improve PFS in patients with PSMA-positive castration-resistant prostate cancer.⁸¹ All of these treatment modalities have demonstrated clinical benefit by targeting specific antigen expression on tumors, suggesting the importance of dissecting molecular features on tumor cells before determining the treatment plan for each patient.

Addressing challenges such as access to genomic profiling testing and the MTB is also important to resolve health care disparities in the United States and globally. Not all institutions have the capacity to conduct MTBs. Inter-institutional collaboration through the establishment of precision medicine networks, the implementation of virtual meetings at the request of physicians, and education and training in MTBs for healthcare providers in rural areas may lead to a seamless discussion with patients regardless of the areas in which they live.

MTBs are an integral part of delivering precision medicine to patients with early and advanced cancer. Its presence and role are growing, and multiple clinical trials are underway to evaluate the feasibility of MTB for the implementation of personalized medicine in oncology. The above challenges need to be addressed to eliminate disparities and advance precision oncology, but the future of precision medicine is bright, and MTB will continue to play an important role in offering the best personalized therapy for patients with cancer.

Summary

With multiple molecular targeted therapies available for patients with cancer that correspond to a specific genetic alteration, the selection of the best treatment through discussion is essential to ensure therapeutic efficacy. MTBs play a key role in this decision-making process to deliver personalized medicine to patients with cancer in a multidisciplinary manner. Historically, personalized medicine has been offered to patients with advanced cancer, but the incorporation of molecular targeted therapies and immunotherapy into the perioperative setting requires clinicians including surgeons to understand the role of the MTB. Evidence is accumulating to support the feasibility and survival benefit in patients treated with the “matched” therapy proposed by the MTB, and the MTB will continue to play an integral role in incorporating the growing body of evidence of cancer therapy to provide personalized treatment for each patient with cancer.

Key Points.

• Clinicians caring for patients with cancer need to understand the process of precision medicine.

• Precision oncology allows for treatment selection based on molecular profiles of each patient’s cancer.

• Precision medicine has been incorporated into both definitive and palliative treatments for patients with advanced malignancies regardless of histologic subtype.

• Molecular tumor boards play an important role in the interpretation of genomic profiling tests and recommendations of molecularly matched treatment regimens.

• Many subspecialists take a vital role in the Molecular Tumor Board in order to discuss the best personalized treatment for each patient with cancer.

Synopsis:

With multiple molecular targeted therapies available for patients with cancer that correspond to a specific genetic alteration, the selection of the best treatment through discussion is essential to ensure therapeutic efficacy. MTBs play a key role in this decision-making process to deliver personalized medicine to patients with cancer in a multidisciplinary manner. Historically, personalized medicine has been offered to patients with advanced cancer, but the incorporation of molecular targeted therapies and immunotherapy into the perioperative setting requires clinicians including surgeons to understand the role of the MTB. Evidence is accumulating to support the feasibility and survival benefit in patients treated with the “matched” therapy proposed by the MTB, and the MTB will continue to play an integral role in incorporating the growing body of evidence of cancer therapy to provide personalized treatment for each patient with cancer.

Clinics Care Points.

• The MTB is an essential venue for discussing molecular profiling test results and offering personalized therapy including molecular targeted therapy, immunotherapy, and available clinical trials for patients with cancer.

• Precision medicine is being incorporated into the perioperative setting and, therefore, surgical oncologists should be involved in multidisciplinary Molecular Tumor Boards.