Version July 2025
INTRODUCTION —
A subset of cancers express deficient mismatch repair (dMMR) and its characteristic genetic signature, high levels of microsatellite instability (MSI-H) across the genome. Other subsets of tumors express high tumor mutational burden (TMB-H), including most tumors that are dMMR/MSI-H. Tumors that are dMMR/MSI-H and some TMB-H tumors are sensitive to treatment with immune checkpoint inhibitors (ICIs). (See "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'.)
This topic presents the biology, diagnostic testing, and an overview of the management of advanced unresectable and metastatic tumors with dMMR/MSI-H or TMB-H. Specific details on management by primary tumor site may also be found in the relevant UpToDate topics. (See 'Treatment' below.)
TUMORS WITH MISMATCH REPAIR DEFICIENCY —
A subset of cancers express deficient mismatch repair (dMMR) and its characteristic genetic signature, high levels of microsatellite instability (MSI-H) across the genome.
Biologic principles
Pathogenesis — Molecular alterations in one of the deoxyribonucleic acid (DNA) mismatch repair (MMR) genes are found as germline pathogenic variants of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer) and less commonly a somatic (tumor) pathogenic variants. For sporadic colorectal and endometrial cancer, most cases are due to promoter hypermethylation of mutL homolog 1 (MLH1) rather than mutations in a DNA MMR gene [1,2]. (See 'Frequency of dMMR across tumor types' below.)
There are four relevant MMR genes: MLH1, mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2). Further, mutations in the 3' end of the epithelial cell adhesion molecule (EPCAM) gene can cause Lynch syndrome through promoter methylation-induced inactivation of the downstream MSH2 gene. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics' and "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes'.)
MMR is one of a cell's mechanisms for repairing DNA damage. This DNA damage primarily results from single base pair insertions or deletions (called indels) when slippage occurs during DNA replication by DNA polymerases. This type of DNA polymerase error tends to occur in areas of short, repetitive DNA sequences called microsatellites. Therefore, dMMR can be discovered by looking at the variation in the length of a microsatellite in the patient's normal tissue compared with its length in the same patient's tumor tissue. When a high rate of variation in microsatellite length exists across the genome, a tumor is said to have high levels of MSI-H, which reflects an underlying deficiency in MMR capability. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)
The inability to repair DNA damage results in the accumulation of mutations. Tumors that lack the MMR mechanism harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such MMR defects [3,4]. Almost all tumors with dMMR/MSI-H also demonstrate a high tumor mutation burden (TMB-H) [5,6]. However, not all TMB-H cases are MSI-H. (See 'Tumors with high mutational burden' below.)
Response to immunotherapy — Tumors that are dMMR/MSI-H, regardless of the primary tumor site, are particularly responsive to immune checkpoint inhibitors (ICIs), which enhance the immune system's response to tumor neoantigens generated by these cancers. (See 'Treatment' below.)
Therapeutic approaches that harness the immune system to control and treat cancer are known as "immunotherapy." The immune system plays a key role in the surveillance and eradication of malignancy, and tumors often evolve ways to elude the immune system. The same tolerance mechanisms that suppress the immune response to self-antigens to minimize autoimmune disease may also serve to blunt the immune response to these tumor antigens in vivo [7]. (See "Principles of cancer immunotherapy", section on 'Tumor evasion of immune surveillance'.)
Neoantigens generated from tumor-specific mutations of self-antigens within certain cancers may be recognized by the immune system as foreign and could therefore trigger an antitumor immune response. Tumors that are dMMR/MSI-H code for mutant proteins, which, like other cell proteins, are recycled via the immunoproteasome pathway. A minority of these mutations can give rise to neoantigens, or mutation-derived antigens that can be recognized by CD8+ T cells, and targeted by the immune system [8-11]. The greater immunogenicity of mutations generated by dMMR relates to the nature of single base pair insertions and deletions, which lead to frameshift mutations that may generate not one amino acid alteration but a sequence of multiple altered amino acids, creating an amino acid sequence "foreign" to the person. Some of these peptide sequences can then be presented by a person's human leukocyte antigen class I molecules, generating neoantigens for the immune system to target [12].
The immune response generated by tumor neoantigens can be further enhanced by the use of ICIs [13]. Several steps are required for the immune system to effectively attack tumor cells. These include tumor antigen uptake by antigen-presenting cells, such as dendritic cells, presentation of the tumor antigen to T cells, T cell activation and trafficking to the tumor, and direct attack of the tumor. Several immune checkpoints exist to dampen the immune response to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, such immune checkpoints can result in immune tolerance to the tumor allowing escape from the immune response and progression of the malignancy. Therefore, drugs that inhibit these checkpoints are expected to halt or reverse disease progression. Examples of checkpoints that are targeted by ICIs (table 1) include programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), among others. (See "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'.)
Frequency of dMMR across tumor types — The prevalence of dMMR/MSI-H status varies by tumor type.
●Primary tumors – Based on observational data using next generation sequencing (NGS), cancers with the highest frequency of dMMR/MSI-H within the primary tumor (figure 1) are uterine endometrial carcinoma (31 percent), colon adenocarcinoma (20 percent), gastric adenocarcinoma (19 percent), rectal adenocarcinoma (6 percent), adrenocortical carcinoma (4 percent), uterine carcinosarcoma (4 percent), cervical squamous cell carcinoma and endocervical adenocarcinoma (3 percent), Wilms tumor (3 percent), mesothelioma (3 percent), esophageal carcinoma (2 percent), and breast carcinoma (2 percent) [14]. In contrast, dMMR/MSI-H expression was rare among other primary tumor types (less than 2 percent).
●Metastatic disease – The frequency of dMMR/MSI-H expression among metastatic cancers tends to be lower than that of localized tumors, given that dMMR/MSI-H tumors have a lower rate of developing metastases. Based on observational studies using NGS of metastatic tumor types, the cancers with the highest frequency of dMMR/MSI-H (table 2) include endometrial cancer (16 percent), small bowel cancers (16 percent), colorectal cancer (3 to 8 percent), gastric adenocarcinoma (3 percent), esophagus and esophagogastric junction tumors (3 percent), bladder cancer (3 percent), prostate cancer (2 percent), and gastrointestinal neuroendocrine tumors (2 percent) [13,15].
Diagnostic testing for dMMR/MSI-H
Who should be tested? — We test for dMMR/MSI-H in patients with advanced or metastatic solid tumors who are candidates for immunotherapy if found to have dMMR/MSI-H and for whom standard treatment does not already include immunotherapy [16]. Testing for dMMR/MSI-H is also standardly performed for all patients with colorectal and endometrial cancer due to the high rate of Lynch syndrome in these cancer types. However, patients with cancer of any type that is confirmed to express dMMR/MSI-H should undergo a diagnostic evaluation for Lynch syndrome [6]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)
Selecting between tests — Tumor expression of dMMR/MSI-H can be assessed using immunohistochemistry (IHC) for dMMR, DNA polymerase chain reaction (PCR) for MSI-H, or NGS for MSI-H on tumor tissue samples.
●For patients with colorectal cancer, any of these testing methods is acceptable [17]. IHC results for dMMR status are often already available in patients who presented with stage I, II, or III disease, and IHC is performed in patients with de novo metastatic disease who need a rapid test result to initiate therapy. In addition to IHC, we also obtain NGS panels, which can simultaneously assess for other actionable mutations.
●For cancers other than colorectal cancer, we use NGS panels or IHC rather than PCR due to the potentially lower sensitivity of PCR in other tumor types.
Immunohistochemistry — IHC tests for the loss of the various MMR proteins (MLH1, MSH2, MHS6, and PMS2). Mutations in the MMR genes that cause Lynch syndrome and biallelic mutations in MMR genes or hypermethylation of the MLH1 promotor in sporadic dMMR colon cancers typically result in a truncated or lost MMR protein that can be detected as a loss of staining of the protein on tumor IHC (table 3). Further details are discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Immunohistochemistry'.)
PCR — DNA polymerase chain reaction (PCR) can detect microsatellite instability by comparing the variation in length of a limited number of microsatellites between normal and tumor tissue. Microsatellite instability testing is performed using PCR to amplify a standard panel of DNA sequences containing nucleotide repeats. In the most commonly used panel (which includes two mononucleotides [BAT25 and BAT26] and three dinucleotides [D2S123, D5S346, and D17S250] [18-20]), if 30 percent or more of the markers show expansion or contraction of the repetitive sequences in the tumor compared with the normal mucosa from the same patient, the tumor is reported to have MSI-H. These microsatellites were chosen based on the desire to identify the inherited cause of dMMR (Lynch syndrome) in patients with colorectal cancer. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)
Next-generation sequencing — Microsatellite instability testing can also be performed with NGS panels. As there are thousands of microsatellites through the genome that are readily captured with NGS methods, laboratories have developed different methods of gauging the level of variation at these microsatellites. Multiple NGS testing panels are commercially available. These NGS panels determine MSI-H status based on a comparison of the microsatellites sequenced [6,15,21]. In each platform, the specific microsatellites analyzed vary, and the statistical methodologies determining variation in length are unique. However, all these NGS panels have excellent sensitivity and specificity when compared with either PCR for MSI-H [22-24] or IHC for dMMR status.
NGS is the preferred testing option when evaluating for dMMR/MSI-H in noncolorectal cancer. NGS improves detection of MSI-H across different tumor types due to a larger number of microsatellites evaluated. The variation in length of microsatellites is tissue specific, as different tumor types demonstrate different predilections for altered microsatellites. Studies also suggest that a specific, limited PCR panel devised primarily for colorectal cancer would likely demonstrate suboptimal performance across other tumor types. As examples:
●In an exome analysis of 617 gastric, colorectal, and endometrial cases, MSI-H using exome data was compared with that using PCR detection and demonstrated a sensitivity of 95.8 percent and a specificity of 97.6 percent [25]. However, in 7 of the 16 discrepant cases, additional data demonstrated the exome MSI-H determination to be correct and the PCR determination to be incorrect.
●In an observational series of 91 prostate cancer patients, MSI-H by an NGS panel was compared with MSI-H by PCR, using biallelic inactivating mutations in MMR genes as the gold standard. Using this gold standard, 29 patients had dMMR, and 62 had proficient mismatch repair (pMMR). The sensitivity and specificity for detection of dMMR were 93.1 and 94 percent for NGS and 72.4 and 100 percent for PCR [26].
Treatment — ICIs are effective and well-tolerated therapies in advanced or metastatic solid tumors with dMMR/MSI-H [27]. Specific management strategies that incorporate ICIs vary based on the primary tumor site and line of therapy.
Primary site-specific approaches — The following cancer primaries have specific treatment approaches for advanced unresectable or metastatic dMMR/MSI-H disease. Further details with supporting evidence are discussed separately.
●Metastatic colorectal cancer
●Metastatic endometrial cancer
•(See "Initial treatment of metastatic endometrial cancer", section on 'MMR deficient tumors'.)
●Metastatic esophageal and gastric cancer
●Advanced unresectable and metastatic biliary tract cancers
●Metastatic pancreatic cancer
•(See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'MSI-H/dMMR tumors'.)
Primary site-independent approaches — Many patients with advanced or metastatic cancers will have been exposed to ICIs as part of earlier lines of therapy. However, for those with cancers that are dMMR/MSI-H, have been treated with all available primary site-specific therapies, and have not received prior immunotherapy, either pembrolizumab or dostarlimab are appropriate options. These ICIs have received a "tissue-agnostic" drug approval from the US Food and Drug Administration (FDA) due to their efficacy across a wide array of solid tumor types expressing dMMR/MSI-H.
Pembrolizumab — Multiple studies suggest that pembrolizumab is effective and leads to durable responses in a variety of advanced or metastatic dMMR/MSI-H solid tumors [13,28-32]. These findings were subsequently confirmed in a combined analysis of three open-label, single-arm phase I/II clinical trials conducted in 504 patients with various advanced or metastatic dMMR/MSI-H solid tumors (KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051) [33].
●In a phase II trial (KEYNOTE-164), pembrolizumab was evaluated in 124 patients with advanced dMMR/MSI-H colorectal cancer who progressed on treatment with a fluoropyrimidine and either oxaliplatin or irinotecan, with or without antiangiogenic therapy or an epidermal growth factor receptor inhibitor [28,29]. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Pembrolizumab'.)
●In a phase II trial (KEYNOTE-158), pembrolizumab was evaluated in 373 patients with a variety of advanced MSI-H or dMMR solid tumors other than colorectal cancer who progressed on systemic therapy. Patients were either prospectively enrolled (Cohort K) or retrospectively identified (Cohorts A through J) [30,31].
●In phase I/II trial (KEYNOTE-051), pembrolizumab was evaluated in seven pediatric patients with various dMMR/MSI-H tumor types, of whom six had brain tumors, and one had an abdominal adenocarcinoma [32].
At a median follow-up of 20 months (range of 0.1 to 71 months), among all 504 patients pooled from KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051, the objective response rate (ORR) was 33 percent, including a complete and partial response rate of 10 and 23 percent, respectively [33]. Among the 168 patients with an objective response, the median duration of response was 63 months, with durable responses (three years or longer) seen in 39 percent. Objective responses were seen in almost every cancer type (except for mesothelioma); the highest ORRs were seen in colorectal cancer (34 percent), endometrial cancer (33 percent), gastric or gastroesophageal junction tumors (50 percent), and small intestinal cancers (59 percent).
Based on these data, pembrolizumab is approved by the FDA for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options [33].
Dostarlimab — Dostarlimab has effective and durable treatment responses and is well-tolerated in patients with advanced or recurrent dMMR/MSI-H solid tumors.
In an open-label phase I trial (GARNET), 347 patients with advanced or recurrent dMMR and MSI-H or polymerase epsilon-(POLE) altered solid tumors were treated with dostarlimab [34]. Among the 327 patients with dMMR and MSI-H tumors, most had endometrial cancer (43 percent), followed by colorectal cancer (32 percent) and other dMMR tumor types (25 percent; gastric cancer, pancreatic cancer, small intestinal cancer, and ovarian cancer, among others). All patients received at least one prior line of therapy.
At a median follow-up of 28 months, among the 327 patients with dMMR/MSI-H tumors, the ORR was 44 percent, including a complete response rate of 13 percent [34]. Among the 144 patients with an objective response, the median duration of response was not reached, with most patients (72 percent) demonstrating a response lasting one year or longer. Median progression-free survival (PFS) and overall survival (OS) were seven months and not reached, respectively. Among 11 patients with POLE-altered solid tumors, the ORR was 55 percent. Median PFS and OS were 19 months and not reached, respectively. Toxicities for dostarlimab was consistent with those of other PD-1 and PD-L1 inhibitors, with no new safety concerns noted.
Dostarlimab has accelerated approval from the FDA for the treatment of adult patients with dMMR-recurrent or -advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options [33].
Other agents — Other single-agent ICIs that have been evaluated in unselected cohorts of advanced and metastatic dMMR/MSI-H cancer types include nivolumab [35], tislelizumab [36], and serplulimab [37].
TUMORS WITH HIGH MUTATIONAL BURDEN
Biologic principles — Cancers with high tumor mutational burden (TMB-H) are thought to be more immunogenic through the surface presentation of neoantigens [38]. Therefore, some TMB-H tumors may respond to immune checkpoint inhibitors (ICIs) [39-49]. Most tumors that express deficient mismatch repair (dMMR)/microsatellite instability (MSI-H) also have TMB-H, with the median number of mutations often in the thousands. However, not all TMB-H tumors are dMMR/MSI-H, and in such cases, the number of mutations is significantly lower [5]. Approximately 200 nonsynonymous mutations per exome is equivalent to 10 mutations per megabase on the FoundationOne CDx platform [39,40,50,51]. (See "Genetics: Glossary of terms", section on 'Coding mutation, variant, or polymorphism'.)
Most observational studies that include different types of cancer support a correlation between TMB-H and improved responses to ICIs [40,52-58]. However, this relationship is not always consistent across all tumor types (figure 2). For example, some cancers, such as mesothelioma, Merkel cell carcinoma, and renal cell carcinoma [59], demonstrate low to intermediate levels of TMB but are still very responsive to ICIs [41]. In contrast, proficient mismatch repair (pMMR)/microsatellite stable (MSS) colorectal cancer also demonstrate low to intermediate levels of TMB but generally have limited responses to currently approved ICIs [41,60]. (See 'Diagnostic testing for TMB' below.)
Frequency of TMB across tumor types — The average TMB level across all solid tumor types is approximately 13 percent [9]. High levels of TMB are found most frequently in melanoma, cutaneous squamous cell carcinomas, non-small and small cell lung cancer, urothelial carcinoma, and head and neck squamous cell carcinoma (figure 2) [5,9,38,41,61]. High levels of TMB can also be found frequently, but not exclusively, in other primary cancers that are dMMR/MSI-H, such as small bowel adenocarcinomas, colorectal cancer, endometrial carcinoma, esophagus adenocarcinoma, cervical carcinoma, and gastric cancer [62-64]. Intermediate to lower levels of TMB are found in cancers of the breast, ovaries, kidneys, prostate, testicle, colon (pMMR), pancreas, liver, anus, central nervous system; uveal melanoma; mesothelioma; and certain subtypes of soft tissue sarcoma [41].
Diagnostic testing for TMB
Who should be tested? — We test for TMB levels in most patients with advanced or metastatic solid tumors who progress on prior systemic therapy, have no other appropriate treatment options, and are candidates for immunotherapy [16].
Next generation sequencing — We perform next-generation sequencing (NGS) on tumor tissue to assess TMB levels. Test results should always be interpreted in the context of the specific NGS panel being used and the tumor type being evaluated. The FoundationOne CDx assay is approved by the US Food and Drug Administration (FDA) as a companion diagnostic for pembrolizumab to detect TMB-H (ie, ≥10 mutations per megabase in patients with solid tumors) [65]. If a different TMB assay is used, clinicians should review the manufacturer's documentation to confirm the appropriate TMB-H threshold for their tumor of interest.
It is challenging to find an optimal TMB-H threshold to predict response to immunotherapy that applies to all cancers, as such thresholds differ across tumor types [66,67] and testing platforms (eg, tumor tissue versus blood) [68]. In the FoundationOne CDx assay, the definition of TMB-H as ≥10 mutations per megabase was based on the threshold used in a phase II clinical trial (KEYNOTE-158) that included a variety of tumor types [49]. This particular threshold was validated in studies of lung and urothelial cancers, which suggest a correlation between higher TMB levels and response to ICIs [39,50,51,69,70]. However, the optimal TMB threshold for other cancers is uncertain since TMB levels do not always predict response to immunotherapy for all cancers [41]. Furthermore, falsely elevated TMB is possible in patients with cancers where high levels of TMB are not typical, especially when TMB is discordant with dMMR/MSI status (ie, TMB-H is detected in a tumor that is pMMR/MSS), or in individuals of non-European ancestry (due to underrepresentation in genetic reference databases of germline variants) [71]. In such cases, it is useful to consult with a molecular pathologist, if such expertise is readily available, to perform paired tumor-germline testing to distinguish between a true versus false-positive TMB-H test result.
Efforts are ongoing to harmonize TMB assays across different tumor types and testing platforms [66-68,72-74].
Treatment
Pembrolizumab — Pembrolizumab is an option for most patients with advanced unresectable or metastatic TMB-H (≥10 mutations per megabase) solid tumors who have been treated with all available primary site-specific therapies and have not received prior immunotherapy.
Exceptions include the following TMB-H tumors:
●Metastatic colorectal cancer with TMB-H, pMMR, and no polymerase epsilon (POLE) or polymerase delta 1 (POLD1) variant – Although there is debate, we do not routinely offer pembrolizumab to patients with metastatic colorectal cancer that is TMB-H, MSS/pMMR, and lacking a functional POLE or POLD1 pathogenic variant, due to limited efficacy. Further details are discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'TMB-H tumors'.)
The efficacy of pembrolizumab was established in an open-label, single-arm phase II trial (KEYNOTE-158) [49]. The study enrolled over 1000 patients with a variety of advanced unresectable or metastatic solid tumors who had progressed on or were unable to tolerate at least one prior line of systemic therapy. A subset of 102 patients had TMB-H tumors (defined as TMB ≥10 mutations per megabase) and 688 patients had TMB-low tumors (TMB <10 mutations per megabase).
At a median follow-up of 37 months, objective response rates (ORRs) were as follows:
●TMB-H tumors – Among the patients with TMB-H tumors, the ORR was 29 percent. Among the 81 patients with TMB-H and MSS disease, the ORR was 28 percent. For patients with TMB-H tumors, objective responses were seen in those with small cell lung cancer (29 percent), cervical cancer (31 percent), endometrial cancer (47 percent), neuroendocrine tumors (40 percent), vulvar carcinoma (17 percent), anal cancer (7 percent), thyroid cancer (100 percent), and salivary gland cancer (33 percent).
●TMB-low tumors – In contrast, for the 688 patients with TMB-low tumors, the ORR was 6 percent.
Although median progression-free survival (PFS) was similar for both TMB-H and TMB-low tumors (median PFS two months each), the tail of the PFS curve favored TMB-H tumors (three-year PFS 32 versus 22 percent).
Based on the data from KEYNOTE-158, pembrolizumab has received accelerated approval from the FDA for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H (≥10 mutations per megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options [33].
Although the KEYNOTE-158 trial did not include more common tumors (eg, breast, colorectal, gastroesophageal, prostate), subsequent clinical trials have supported the efficacy of pembrolizumab in some of these tumor types with TMB-H. In an open-label, single-arm, phase II basket study (Targeted Agent and Profiling Utilization Registry [TAPUR]), 77 patients with advanced TMB-H cancers (28 with colorectal cancer and 49 with other cancer types) were treated with pembrolizumab [60]. Among those with colorectal cancer, the ORR was 11 percent, most of whom had pMMR/MSS disease; a partial response was seen in one patient with both TMB-H and a POLE mutation. Among the pooled cohort of 47 evaluable patients with noncolorectal cancers, the ORR was 26 percent, including three complete responses (bladder cancer, cutaneous squamous cell carcinoma, parotid cancer) and nine partial responses (two patients with neuroendocrine carcinoma, two with nonmelanoma skin cancer, and one patient each with head and neck cancer, prostate cancer, porocarcinoma, small cell lung cancer, and cervical cancer). In a separate TAPUR study of patients with metastatic TMB-H breast cancer treated with pembrolizumab, the ORR was 37 percent [75].
However, not all studies support the efficacy of pembrolizumab across every TMB-H solid tumor type, particularly for those that are pMMR/MSS [43,76]. As an example, in a phase II TAPUR basket study, the objective responses to pembrolizumab were limited in the patients with colorectal cancer, most of whom had pMMR/MSS disease (11 percent) [60]. However, in patients with metastatic colorectal cancer that are TMB-H (≥10 mutations per megabase) and pMMR, data suggest that pathogenic variants in the POLE and POLD1 genes are associated with increased responses to ICIs [76-78]. Further details are discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'TMB-H tumors'.)
Other agents — Studies are mixed for the benefits of combination immunotherapy, such as nivolumab plus ipilimumab in metastatic TMB-H solid tumors, and further data are needed. Although a meta-analysis suggests that TMB predicts benefit for combination immunotherapy [57], individual studies have not always shown this association [40].
SUMMARY AND RECOMMENDATIONS
●Tumors with dMMR/MSI-H
•Biologic principles – A subset of cancers express deficient mismatch repair (dMMR) and its characteristic genetic signature, high levels of microsatellite instability (MSI-H) across the genome. Tumors that are dMMR/MSI-H, regardless of the primary tumor site, are particularly responsive to immune checkpoint inhibitors (ICIs). (See 'Tumors with mismatch repair deficiency' above and 'Response to immunotherapy' above.)
•Frequency – Among patients with metastatic cancer, cancers with the highest frequency of dMMR/MSI-H include endometrial cancer, small bowel cancers, and colorectal cancer (figure 1 and table 2). (See 'Frequency of dMMR across tumor types' above.)
•Who should be tested? – We test for dMMR/MSI-H in patients with advanced or metastatic solid tumors who are candidates for immunotherapy if found to have dMMR/MSI-H and for whom standard treatment does not already include immunotherapy. Testing for dMMR/MSI-H is also standardly performed for all patients with colorectal and endometrial cancer due to the high rate of Lynch syndrome in these cancer types. However, patients with cancer of any type that is confirmed to express dMMR/MSI-H should undergo a diagnostic evaluation for Lynch syndrome. (See 'Diagnostic testing for dMMR/MSI-H' above and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)
•Treatment of advanced or metastatic disease – Certain cancer primaries have specific treatment approaches for advanced unresectable or metastatic dMMR/MSI-H disease (eg, colorectal cancer, endometrial cancer, esophageal and gastric cancer, biliary tract cancers, and pancreatic cancer). These approaches are discussed separately. (See 'Primary site-specific approaches' above.)
For other cancers that are dMMR/MSI-H, have been treated with all available primary site-specific therapies, and have not received prior immunotherapy, either pembrolizumab or dostarlimab are appropriate options. (See 'Primary site-independent approaches' above.)
●Tumors with TMB-H
•Biologic principles – Cancers with high tumor mutational burden (TMB-H) are thought to be more immunogenic through the surface presentation of neoantigens, and some may respond to ICIs. Most tumors that express dMMR/MSI-H also have TMB-H, but not all TMB-H tumors are dMMR/MSI-H. (See 'Biologic principles' above.)
•Frequency – High levels of TMB are found most frequently in melanoma, cutaneous squamous cell carcinomas, non-small and small cell lung cancer, urothelial carcinoma, and head and neck squamous cell carcinoma. It can also be found frequently, but not exclusively, in other primary cancers that are dMMR/MSI-H, such as small bowel adenocarcinomas, colorectal cancer, endometrial carcinoma, esophagus adenocarcinoma, cervical carcinoma, and gastric cancer. (See 'Frequency of TMB across tumor types' above.)
•Who should be tested? – We test for TMB levels in most patients with advanced or metastatic solid tumors who progress on prior systemic therapy, have no other appropriate treatment options, and are candidates for immunotherapy. (See 'Diagnostic testing for TMB' above.)
•Treatment of advanced or metastatic disease – For most patients with advanced unresectable or metastatic TMB-H (≥10 mutations per megabase) solid tumors who have been treated with all available primary site-specific therapies and have not received prior immunotherapy, pembrolizumab is an appropriate option. (See 'Pembrolizumab' above.)
