CA Heavyweight Clinical Management Strategy for Precise Treatment of Metastatic Colorectal Cancer in the Era

Colorectal cancer (CRC), which accounts for about 10% of all cancers, is the second most common cause of cancer deaths, with about 1.
9 million new CRCs and about 900,000 deaths
worldwide in 2020.
Because CRC is initially insidious and difficult to distinguish from other diseases, about 20% of patients have developed metastatic colorectal cancer (mCRC)
at initial diagnosis.
In addition, as the course of the disease progresses, about 50% of patients with localized CRC have tumors that metastasize and progress to mCRC
.

Over the past 20 years, with the introduction of a variety of therapeutic methods such as liver and lung metastasis surgery, targeted therapy, and immunotherapy, the prognosis of patients with mCRC has improved
significantly.
However, in most cases, mCRC is still regarded as an incurable disease, so how to properly manage mCRC patients is a highly practical and highly challenging medical problem
.
Based on the above background, the Journal of the American Cancer Society CA: A Cancer Journal for Clinicians (IF: 286.
13) recently published a review summarizing the improvement of clinical management in mCRC patients in the era of precision medicine
.

At present, researchers have identified three molecular pathogenic pathways in the pathogenesis of CRC, namely chromosomal instability (CIN), highly microsatellite instability (MSI-H), and CpG island methylation phenotype (CIMP
).

CIN refers to the change in the number of chromosomes, chromosome amplification, and/or heterozygous deletion due to the abnormal accumulation of all or most of the chromosomes due to the acquisition or loss, and is a classic molecular model
of the development of "normal mucosal epithelium-adenoma-adenocarcinoma" in colorectal cancer.

In addition, about 15%-20% of CRCs have the MSI-H phenotype, and microsatellites are a class of simple tandem repeats with high mutation rates
.
Under normal circumstances, the mismatch repair gene corrects the mismatch of the microsatellite and maintains genetic integrity
.
When there is a mismatch repair deletion (dMMR) and the gene correction mechanism fails, the MSI-H phenotype appears, which induces the inactivation of multiple tumor suppressor genes and the activation of proto-oncogenes such as BRAF, which in turn leads to colorectal cancer
.

The serrated oncology pathway is the third pathogenic pathway
of CRC.
The epigenomic instability of serrated tumors is closely related to the methylation disorder of CpG islands, and CIMP can lead to abnormally high methylation of the promoter region of the tumor suppressor gene, which in turn leads to the silencing of tumor suppressor genes and promotes tumor development
.
In addition, a subgroup of MSI-H tumors may also exhibit features
of jagged tumors.

The purpose of the analysis of the mCRC gene mutation map is to implement a truly personalized treatment based on precision medicine for each patient, however, the development of precision treatment for mCRC patients is more challenging
than expected.
This is partly due to the genetic heterogeneity of tumors, the lack of drug-producing targets, and the complex interactions between different signaling pathways that may allow cancer cells to evade single-target inhibition effects
.
At present, the research on the mCRC gene mutation map mainly focuses on the following aspects
.

Epidermal growth factor receptor (EGFR)

First of all, in more than 20 years of research, the EGFR family and its intracellular signaling pathway have been the cornerstone of mCRC targeted therapy, EGFR belongs to the cell membrane growth factor receptor family with tyrosine kinase activity, which can regulate the proliferation, migration, invasion and induction of tumor angiogenesis
through the RAS-RAF-MEK-MAPK and PTEN-PI3K-AKT-mTOR pathways.

Figure 1 The EGFR and HER2 pathways in mCRC

RAS pathway

The RAS family consists of 3 different genes that encode a total of 4 proteins: HRAS, NRAS, KRAS4A and KRAS4B, of which KRAS4B is also referred to as KRAS
.
The KRAS activation mutation was the first predictive-negative biomarker for mCRC anti-EGFR therapy, and subsequent studies have confirmed that NRAS mutations can also make mCRC resistant to anti-EGFR therapy
.
More than 40% of mCRCs have KRAS mutations, while NRAS mutations are rarer, accounting for about 5%-10%
of mCRCs.

BRAF mutation

BRAF mutations are observed in about 10%-15% of mCRCs, with V600E being the most common BRAF mutation
.
BRAF mutations are mutually exclusive with KRAS and NRAS mutations, but can also lead to resistance to anti-EGFR therapy
.
BRAF V600E mutations are more common in older age, women, and patients with right-sided tumors
.
Retrospective studies have shown that non-BRAF V600E mutant mCRC has a longer overall survival (OS) compared to BRAF V600E mutations, but non-BRAF V600E mutations are rare, occurring only in
about 2% of cases.

HER2 mutation

HER2 mutations are relatively rare in mCRC, with overexpression of the HER2 protein due to amplification of the HER2 gene present in approximately 3% of mCRC patients, and are mainly seen in patients with
RAS/BRAF wild-type mCRC.

MSI-H/dMMR

MSI-H/dMMR is present in about 15%-20% of mCRCs and is associated with tumor stage: about 20% of stage II tumors, about 12% of stage III tumors, and about 5%
of stage IV tumors.
For patients with MSI-H/dMMR, immune checkpoint inhibitors have strong anti-tumor activity, so it is strongly recommended that each mCRC patient undergo tumor microsatellite status assessment
.

Other rare mutations

Other rare mutations, including ALK, ROS1, NTRK, and POLE, are present in about 0.
2%-2.
4% of mCRCs
.

Transcriptome analysis of tumor cells, tumor infiltration matrices, and gene expression in the tumor microenvironment showed that CRCs can be divided into four consensus molecular subtypes (CMS).

。 Among them, CMS1 tumors (MSI-H immune type, occurring in about 14% of early CRCs) are hypermutant and highly methylated tumors, with BRAF V600E mutation enrichment status, and show strong immunoinfiltration; CMS2 tumors (typical tumors, occurring in about 37% of early CRCs) are epithelial tumors characterized by activation of the WNT and MYC pathways; CMS3 tumors (metabolic, occurring in about 13% of early CRCs) often have KRAS mutations and unregulated tumor cell metabolic pathways; CMS4 tumors (mesenchymal type, occurring in about 23% of early CRCs) are characterized by EMT-related activation
of the pathway.

In terms of patient characteristics and prognosis, CMS1 tumors are common in patients with primary female right tumors, with undifferentiated histopathological manifestations and poor prognosis after recurrence; CMS2 tumors are often localized to the left side of the colon or rectum and have a better prognosis; CMS4 tumors are often diagnosed in the late stages of the disease, and their recurrence-free survival (RFS) and OS are poor
.

It is worth noting that CRC patients do not have only one CMS, and studies have found that about 55% of tumor samples can identify ≥ 2 CMS groups, a phenomenon known as intra-tumor CMS heterogeneity
.
Intratumor CMS heterogeneity may be the result of tumor biology and interactions between cancer cells and the microenvironment, and is associated
with decreased disease-free survival (DFS) and OS.

In the treatment of mCRC, in addition to chemotherapy, molecularly targeted drugs [including anti-vascular endothelial growth factor-A (anti-VEGF-A) and anti-EGFR monoclonal antibodies, etc.
] have been applied
in the selection and improvement of better treatment regimens.
The increasing number of effective anticancer drugs, coupled with improved surgery and the availability of local ablation therapy for liver and lung metastases, has significantly improved
patient survival rates under a variety of ongoing treatment strategies.
In addition, up to one-third of mCRC patients confined to the liver (and in some cases to the lungs) can even be cured with systematic pharmacotherapy and comprehensive clinical management of local radical surgery to remove metastases
.

There are already multiple treatment options available for mCRC patients including chemotherapy, targeted therapy, and immunotherapy (Figure 2), and the combination of local treatments such as surgery and ablation therapy has significantly improved the survival benefit of mCRC patients
.

Figure 2 Common drugs for mCRC patients, the year indicates the FDA approval time for the drug's first mCRC indication

In the early days, mCRC patients mainly rely on the treatment of cytotoxic drugs, and the widespread application of programs such as 5-FU+LV+oxaliplatin (FOLFOX) and 5-FU+LV+ irinotecan (FOLFIRI) improves the patient's OS
.
With the change of treatment concept, molecular targeted drugs such as anti-angiogenic drugs and anti-EGFR monoclonal antibodies have gradually been introduced into the treatment of mCRC, mainly including the following categories
.

Anti-angiogenesis therapy

Anti-angiogenesis therapy is the first biological therapy that can synergize chemotherapy
to exert anti-tumor effects.
Tumor-induced angiogenesis is a marker of the development of all solid tumors, including CRC, and bevacizumab, a humanized anti-VEGF-A monoclonal antibody, is the first antiangiogenesis drug
to enter the clinical treatment of mCRC.
Multiple phase II and III studies have demonstrated that the addition of bevacizumab to 5-FU-based chemotherapy improves PFS and OS
in mCRC patients.
In addition to bevacizumab, abercept, remoxizumab, and regofinib have also been used in
the second- and third-line treatment of mCRC.
However, although anti-angiogenic drugs have been studied for 20 years, no recognized biomarkers of efficacy prediction have been found, so similar to chemotherapy, such drugs are still used in patients with
unselected mCRC.

Anti-EGFR therapy

Unlike anti-angiogenesis therapy, the anti-EGFR monoclonal antibodies cetuximab and panimumab are reserved for mCRC patients with specific genotypes, i.
e.
, RAS/BRAF wild-type patients
.
Both the FDA and the European Medicines Agency (EMA) require target mutacity analysis
of KRAS, NRAS, and BRAF before mCRC patients are treated.
Chemotherapy plus cetuximab or panimumab has become the first-line standard of care for patients with wild type RAS/BRAF, and can also be used as a second-line treatment
after chemotherapy plus bevacizumab in such patients.
It is important to note that anti-EGFR monoclonal antibody combined chemotherapy typically performs well in patients with left-sided colon or rectal cancer, but patients with right-sided colon cancer are less
sensitive to this treatment regimen due to different gene expression profiles.

For patients with RAS/BRRA wild-type left-sided colon or rectal cancer, anti-EGFR therapy achieves objective remission in about two-thirds of patients, with a median PFS of up to 11 months, but patients still develop disease progression
.
In patients with progression, the usual regimen is to switch between chemotherapy backbones by adding antiangiogenesis agents, but a growing body of clinical research suggests that re-application of anti-EGFR therapy may be effective
.
Studies have suggested that during second-line therapy without the use of anti-EGFR drugs, the replicated fragments of acquired RAS mutation resistance will gradually decay (half-life is about 4 months), while the wild sequence of RAS/BRAF may proliferate, thereby restoring sensitivity to anti-EGFR drugs, so the concept of anti-EGFR treatment re-challenge has emerged, and several clinical studies are currently evaluating
this.

BRAF targeted therapy

The prognosis of patients with BRAF V600E mutant mCRC is extremely poor, and the median OS of the chemotherapy regimen is only 12 months, so anti-BRAF targeted therapy is also one of the important exploration directions in the era of
precision treatment.
Existing studies suggest that the efficacy of anti-BRAF monotherapy is extremely limited, which may be related
to the cancer cell escape mechanism of BRAF-mutant CRC.
The phase III study BEACON CRC showed that the selective BRAF inhibitor encorafenib combined with cetuximab significantly improved the objective response rate (ORR), PFS, and OS
in patients with BRAF V600E mutant mCRC after first- or second-line therapy failure.
However, on the basis of this regimen, whether combined chemotherapy can benefit patients first-line treatment is still under evaluation in
clinical trials.

Anti-HER2 therapy

Trastuzumab plus lapatinib is the first effective treatment option
for some patients with RAS/BRAF wild-type mCRC who have HER2 amplification.
In addition, regimens and drugs such as trastuzumab plus pattuzumab, trastuzumab plus tucatinib, and antibody drug conjugate Trastuzumab deruxtecan (T-DXd) have also attracted much attention
.
The efficacy of anti-HER2 therapy in chemotherapy-refractory patients has been recognized, and several trials are evaluating its antitumor effects
in the early stages of first-line therapy.

KRAS targeted therapy

As mentioned earlier, the KRAS mutation is the most common cancer-causing mutation in mCRC (incidence > 40%)
.
However, for a long time, none of the drug development of KRAS inhibitors has been successful, so the target was once considered a "non-drug-making target"
.
However, with the deepening of research, KRAS G12C inhibitors gradually came to the stage, and the selective irreversible inhibitors sotorasib and adagrasib developed for this target have been approved by the FDA for the treatment of KRAS G12C mutant advanced lung cancer
.
The data show that the KRAS G12C mutation occurs in about 3%-4% of mCRCs, and a number of studies are currently evaluating
the efficacy of these two drugs combined with anti-EGFR monoclonal antibodies for second- and third-line treatment in mCRC patients.
This may be the beginning of a new therapeutic era, but it is clear that targeted therapies for typical KRAS mutations remain one
of the most important medical needs in the clinical treatment of mCRC.

NTRK targeted therapy

NTRK fusion is a relatively rare gene mutation in mCRC, and the FDA and EMA have approved indications for 2 NTRK inhibitors (emtricitinib and larotinib), which provides more treatment options
for mCRC patients with NTRK fusion.

The introduction of immune checkpoint inhibitors is a revolution in the process of mCRC precision therapy, MSI-H/dMMR is the first efficacy prediction biomarker of mCRC immunotherapy, and there are a large number of neoantigens in this type of tumor, which can increase immunogenicity and are associated with a high immunoinvasive state in the tumor microenvironment, thereby facilitating the treatment
of immune checkpoint inhibitors.

Currently, two anti-PD-1 monoclonal antibodies Pabolizumab and navurizumab, and a combination regimen of navolumab with anti-CTLA-4 monoclonal antibody ipimuzumab has been approved by the FDA for the treatment
of patients with MSI-H/dMMR mCRC.

According to the CMS classification, MSI-H/dMMR type mCRC belongs to the immune-activated CMS1 subgroup
.
For the CMS2 and CMS3 subgroups, known as "immune deserts", and the CMS4 subgroup represented by the "inflammatory microenvironment", the efficacy of immunotherapy is not satisfactory
.

Therefore, the main existing challenge in the clinical treatment of mCRC is to find new therapeutic strategies so that immunotherapy can also play an effective role in mCRC patients with "immune desert" type and the presence of "inflammatory microenvironment", including in combination with anti-angiogenic drugs, with anti-EGFR monoclonal antibodies, with signal transduction pathway inhibitors, and with radiotherapy
.
Some research protocols have demonstrated good anti-cancer activity, but further translational and clinical studies are needed to select the most effective combination strategy and to determine the patient population
for which this protocol will benefit.

The current treatment strategy for mCRC is mainly shown in Figures 3 and 4, but the molecular stratification on which this treatment strategy relies does not fully reflect the complexity and heterogeneity
of the genotype of the disease.
In the future, in order to implement a more precise and personalized treatment for each patient, researchers need to analyze
this in more detail.

Figure 3 First- and second-line treatment of mCRC patients

Figure 4 Post-line treatment of mCRC patients

The future clinical management of mCRC patients should be based on the full integration of tumor gene mutations, tumor and microenvironment gene and protein expression, patient immunity, and the dynamic changes of the above factors throughout the disease process to truly achieve continuous treatment
based on precision medicine.

References

Ciardiello, F.
, Ciardiello, D.
, Martini, G.
, Napolitano, S.
, Tabernero, J.
and Cervantes, A.
(2022), Clinical management of metastatic colorectal cancer in the era of precision medicine.
CA A Cancer J Clin, 72: 372-401.

Editor: Traveler

Reviewer: Jiang Zhou

Typesetting: Youshi

Executive: Tourist