What Precision Oncology Needs to Face in the Next Decade

Preface

Paul Ehrlich conceived a magical bullet targeting microorganisms about a century ago, which is being applied to modern oncology: targeting tumors and the surrounding microenvironment that promotes growth without causing damage to normal tissues. The technological advancements made over the past thirty years, including next-generation sequencing (NGS) technology and advancements in computing power of related bioinformatics algorithms, are making this goal a reality.

In 2001, the first sequencing of the human genome took about 13 years and cost about 2.7 billion US dollars, but now, sequencing can be completed in just a few hours, at a very small cost. This enables sequencing to be used to identify oncogenic gene drivers in individual patients and even different clone populations of tumors, thereby selectively selecting drugs, significantly improving the prognosis of certain cancers.

However, despite substantial progress in cancer treatment, we have even been able to find "panacea" for some types of cancer through the use of genomics and precision oncology treatments. However, precise targeting of solid cancer has not yet produced any universally reactive results, and the response is not as persistent. In the next decade, precision oncology will face six challenges that must be addressed to optimize its application in solid tumors, which is also the Sphindacus mystery that we all need to face.

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Puzzle 1: How to Grasp the Timing of Treatment?

Today, precision targeted therapy for solid tumors is applied to advanced tumors that exhibit multiple common driving factors. Almost all targeted treatments for solid cancer are aimed at patients with advanced metastatic diseases who have undergone extensive pre-treatment. Although some of these patients have reactions, the reactions are often brief. Before the complex clonal evolution of malignant tumors occurs, early application of treatment in the disease course may be crucial for improving the success rate of targeted therapy for solid cancer. Therefore, analyzing molecular genetic damage in tumors should be considered as a first-line strategy for all cancer patients to ensure early and accurate treatment: providing the right drugs to the right patients at the right time. To answer this mystery, carefully designed clinical trials are needed to further study matched targeted drugs in the early stages of solid tumor development.

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Puzzle 2: When Does a Harmful Mutation Cause Disease?

This key puzzle is related to malignant transformation, which involves obtaining somatic mutations that transform healthy cells into cancer cells. At present, there have been a large number of studies on cancer genomics and transcriptomics. Surprisingly, harmful genomic mutations can be seen in non malignant diseases, which makes us confused about which molecular abnormalities to target when treating malignant tumors.

Therefore, it is necessary to carefully confirm the role of harmful mutations in leading to cancer. New data suggests that the explanation for the pathogenicity of mutations goes beyond determining whether mutations cause harmful functional changes. For example, it has been confirmed that harmful mutations in cancer driver genes have also been found in healthy tissues. A genome-wide sequencing study of healthy colon crypts in patients aged 50 to 60 showed approximately 3,000 replacement mutations and 300 deletion mutations, compared to an average of 10,000-20,000 replacements and 1,000-2,000 deletion mutations in most colorectal cancers. In addition, the BRAFV600E mutation is another notable example. These mutations are markers of approximately 50% of melanoma and many other cancers, and are a pathogenic driving factor. However, it is puzzling that they also exist in approximately 80% of benign nevi, and the risk of cancer transformation is negligible.

Therefore, at a fundamental scientific level, the above observations raise the question of what molecular events are actually required for cells to transform into malignant cancer cells? This fully emphasizes the complexity of assessing genomic changes when evaluating treatment goals, and the need to fully understand the environment in which harmful mutations synergistically lead to cancer.

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Puzzle 3: Does Cancer Mutation Have Tissue Tropism?

One of the most interesting features of precision oncology is its tissue agnostic approach. Several mutations found in specific tissues have successfully targeted cancer in other areas. In fact, molecular aberrations in tumors may be as important, or even more important, as their originating tissues.

BRAF mutations are often considered an exception to the tissue agnostic paradigm, as targeting these mutations is an effective strategy for hair cell leukemia and melanoma, while colorectal cancer with BRAF mutations has a poorer response to BRAF inhibitors. However, the poor response to BRAF inhibition in BRAFV600E colorectal cancer is due to the reactivation of the MAPK pathway mediated by EGFR. When targeting the co activation pathway, BRAF inhibitors are effective in colorectal cancer. This discovery ultimately led to the approval of the combination therapy of BRAF inhibitor Encorafenib and EGFR inhibitor Cetuximab for BRAF mutated colorectal cancer. Therefore, molecular aberrations may be the foundation of new cancer pathology.

Another example is the BCR-ABL translocation, which is a hallmark of CML and is rarely found in other cancers except for Philadelphia positive acute leukemia. However, a recent noteworthy report describes the beneficial treatment of BCR-ABL inhibitor imatinib in patients with glioblastoma with BCR-ABL mutations. Overall, the above examples indicate that predicting the potential genomic basis of a single cancer solely based on the site of origin is very difficult. Therefore, universal NGS detection for each tumor is a reasonable solution.

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Puzzle 4: Which Tumor Clone Should Be Targeted?

Cloning evolution is one of the most important features of cancer and currently cannot be treated. During this process, the loss of DNA integrity monitoring mechanisms, such as those caused by TP53 mutations, is an important feature of malignant progression. Clonal growth under treatment pressure is the main cause of recurrence and treatment resistance, making it an important treatment challenge.

From the perspective of precision oncology, this concept is particularly important because actionable targets identified through genomic testing typically represent subclonal events that only exist in a small subset of tumor cells, and genomic changes identified in large tissue NGS may be unrelated to certain parts of the tumor. Therefore, the success of precision oncology largely depends on how many clones can be targeted simultaneously while avoiding treatment-related toxicity.

The effect of targeting a single clone in a tumor composed of multiple clones on sisters clones is not clear. It is conceivable that once a clinically targeted clone is cleared, the competition for oxygen or nutrition between sisters clones can be alleviated, which may accelerate the growth of non targeted clones, thus benefiting from competitive advantages, thus promoting the growth of the whole tumor. This mixed reaction is an important challenge in precision oncology.

The impact of targeted specific mutations on the overall phenotype of tumors remains to be fully elucidated. Research on myeloproliferative tumors has shown that the acquisition order of a given set of mutations strongly affects the phenotypic outcomes of the disease, and therefore may be important in targeted therapy for one or more genomic aberrations. In addition, the concept of hierarchy implies that mutations with higher allele frequencies may be more important for tumors than mutations with lower alleles.

Finally, the concept of targeted convergence pathways may be questioned as different clones may have overlapping and different molecular changes, as activated mutations in different clones cannot converge. Single cell molecular analysis may help reveal changes that occur simultaneously or originate from different cells within the same cell. In the latter case, the treatment plan may involve directly targeting altered gene products or optimizing drug combinations for disrupting key malignant clones.

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Puzzle 5: What Else Do We Need to Consider for Patients?

Oncologists have begun to consider patient demography more carefully, because it is increasingly clear that the incidence rate of cancer and the genetic landscape of cancer vary greatly in different genetic backgrounds and geographical locations, which may be due to different lineage tendencies and exposure to different infectious and toxic substances. In addition, considering biological gender and age is crucial for optimizing precise oncology, because treatment response rate and incidence rate vary between genders, but the therapeutic significance of these factors has not been fully recognized. Finally, individual specific lifestyles, such as those related to smoking or specific western diets, may fundamentally increase the risk of cancer, and the consequences of these lifestyles should be further studied in terms of tumor genetic landscape and sequencing.

Another key extra tumor variable is the microbiota. Many associations related to cancer have been published, but functional studies linking specific microbial species to phenotypes are still scarce. In addition, the microbiota may play a role in determining the outcome of specific genomic abnormalities, such as the impact of TP53 mutations. Depending on the local microbiota, TP53 mutations may play a pro tumor or anti-tumor role. The gut microbiota may also affect the outcomes of checkpoint blockade and chimeric antigen receptor T cell immunotherapy. Nowadays, the importance of microbiota in the efficacy of immunotherapy has been increasingly accepted.

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Puzzle 6: What Is the Correct Timing for Immunotherapy?

A key aspect of cancer immunotherapy is the approval of the anti-PD1 antibody pembrolizumab for the treatment of tumors with high tumor mutation burden (TMB) and microsatellite instability/mismatch repair genetic defects, which are most likely to respond to immune checkpoint blockade. The potential biology behind high TMB tumor reactivity may be that multiple mutations can only exist by utilizing checkpoints that inactivate the immune system, and once these checkpoints are blocked by inhibitors, the immune system will be reactivated. In addition, tumors with higher mutation loads may present more mutated derived new antigens, thereby increasing the immunogenicity of the tumor. However, we lack an accurate understanding of other factors that may play an important role in achieving effective immunotherapy for cancer.

Although high expression of TMB and PD-L1 is important in clinical decision-making, the use of immunotherapy should be accompanied by sound diagnostic criteria to ensure targeting the correct checkpoints. Mutation derived new antigens must have immunogenicity, and the patient's major histocompatibility complex must be able to fully present the new antigen and recognize the presented new antigen.

The efficacy of checkpoint blockade in high TMB cancers is compared to the effectiveness of gene targeted therapy, which seems to be most successful in cancers such as CML driven by individual gene changes. However, the combination of immunotherapy and gene targeted therapy can demonstrate high efficacy. It is currently unclear whether immunotherapy works in synergy with other therapies in these situations, or whether different subgroups of patients are affected differently by these combination drugs.

Finally, first-line immunotherapy is being approved for an increasing number of cancer types. In a recent study, using the anti PD1 antibody dostarlimab as a neoadjuvant therapy for rectal cancer patients, all 12 patients achieved complete remission, indicating that more research is needed to apply immunotherapy in the early stages of the disease.

Summary

The key goal of cancer treatment is to develop therapies specifically targeting cancer cells without causing harm to normal tissues. Two main methods have begun to achieve this goal: gene targeted therapy and immunotherapy. These methods differ in strategy and the types of cancer most susceptible to their impact, therefore, the success of precision treatment in the future will require giving the right drugs to the right patients at the right time.

As our research on the cancer genome deepens, confusion also arises. For example, carcinogenic drivers have been found in various non malignant diseases, which raises the question of how to determine whether harmful genetic changes are truly pathogenic. In addition, other key issues in the context of cancer also involve the role of the originating tissue in cancer, how it affects the biological significance of genomic mutations, how the host's genome and other characteristics affect treatment outcomes, and which clones are the best targets.

A comprehensive answer to these questions requires individualized functional and phenotypic characterization of the host and cancer, using advanced analytical tools to determine how to best target the tumor while minimizing damage to the patient's normal tissue. In the next decade, answering such questions will guide us to open up new fields of precision oncology and make new breakthroughs in cancer treatment.

Reference:

1.The coming decade in precision oncology: six riddles. Nat Rev Cancer.2022 Nov 24.