Current FDA-approved medications for the treatment of metastatic colorectal cancer include two monoclonal antibodies (cetuximab, panitumumab) that selectively inhibit EGFR (epidermal growth factor receptor). A member of the Type I receptor tyrosine kinases, EGFR is a transmembrane glycoprotein known to operate in multiple signaling pathways including vascular endothelial growth factor production, cell growth, and induction of apoptosis. Cetuximab and panitumumab competitively inhibit epidermal growth factor binding, preventing the growth and survival of EGFR-expressing tumor cells (FDA, 2004). Clinical usage of the medication has been limited due to drug resistance to wild-type RAS subpopulations. Upon review of additional tumor gene subpopulations, APC gene status was identified as a key prognostic indicator of EGFR-inhibitor efficacy. APC and TP53 doubly mutated tumors showed the greatest sensitivity to EGFR-inhibitors, while mutated APC tumors also possessed a significant sensitivity compared to wild-type APC tumors, increasing the potential for wider clinical implementation in metastatic colorectal cancer therapy (Yang et al., 2019).

Members of the PARP family, tankyrase enzymes one and two play a key role in WNT signaling and beta-catenin transcriptional activation. Recognized as therapeutic targets, inhibition of these enzymes leads to reduced beta-catenin translocation and subsequent cell death in cells harboring APC mutations. Recent work by Schatoff et al. (2019) identified variable response rates to TNKS-inhibitors based upon tumor APC genotype. ‘Early’ truncating APC mutations were found to be highly resistant to TNKS inhibition, while variants within the mutation cluster region (amino acids 1250–1580) revealed sensitivity. These results differ from earlier studies (Tanaka et al., 2017), which proposed all APC variant cells were sensitive to TNKS-inhibitors. TNKS-inhibitors may offer patients possessing germline APC variants a unique therapeutic option beyond colon resection.

Both NSAIDs and selective COX-2 inhibitors (COXIBs) are known to reduce the incidence and mortality of numerous cancers. Known primarily as critical enzymes in the eicosanoid pathway, Cyclooxygenase-1 (COX-1) and COX-2 complete the two catalytic steps required for the conversion of arachidonic acid into prostaglandin H2. Aspirin covalently and irreversibly binds to COX-1 and COX-2, while other NSAIDs reversibly inhibit these enzymes preventing the downstream signal from inducing inflammation, fever, and prothrombotic events (Kemp Bohan et al., 2020). Also found to contribute a role in cell cycle progression, increased COX-2 expression resulting from upregulation of the Wnt/B-catenin signaling pathway as a key contributing factor in the formation of gastrointestinal polyps. Thus, COX-2 has become a promising target for patients with FAP (McLean et al., 2008; Nuñez et al., 2011). Celecoxib was the first COXIB to be approved as adjuvant therapy for FAP patients by the Food and Drug Administration in 1999, but follow-up investigations revealed an array of toxicities with prolonged time courses, including gastrointestinal bleeding, renal dysfunction, cardiovascular death, myocardial infarction, and stroke (FDA, 2018; Kemp Bohan et al., 2020). Studies involving the use of aspirin as a chemopreventive therapeutic agent have yielded more promising results. In a randomized control trial, Burn et al. (2011) investigated a 600 mg aspirin daily regimen with and without starch in FAP patients. Though the study revealed no reduction in risk of colorectal polyps, there was a statistically significant reduction in polyp diameter in patients treated for at least 1 year. A recent randomized controlled trial in Japan reported FAP patients experienced safe and effective suppression of recurrence for colorectal polyps greater than 5.0 mm when treated with low dose aspirin (Ishikawa et al., 2021). Similarly, a recent meta-analysis estimates a nearly 20% reduction in mortality for all cancer patients who take aspirin (Elmwood et al., 2021). Additionally, for FAP patients experiencing duodenal polyps, a phase II study using a treatment regimen of sulindac and erlotinib resulted in a 71% reduction in duodenal polyp burden, while simultaneously reducing colorectal adenoma burden (Samadder et al., 2018). Aspirin represents a potentially viable option for chemopreventive treatment for FAP patients due to its suppressive effects on large polyp recurrence, mortality reduction, and well tolerated long-term safety profile.

The protective role of oral contraceptives (OCPs) in the risk reduction of ovarian cancer has been well documented in the general population. Studies investigating the role of BRCA1/2 in response to oral contraceptives revealed a similar but weaker risk reduction compared to the general population. Despite the protective effects, BRCA1/2 germline carriers are in a unique clinical conundrum as the use of OCPs possesses a theoretical increased risk of breast cancer. Because studies are unable to fully exclude an increased risk of breast cancer, use of OCPs must be carefully considered within the clinical context (Narod et al., 2002; McGuire et al., 2004; Whittemore et al., 2004; Iodice et al., 2010; Huber et al., 2020).

Used clinically as an ovulatory stimulant, clomiphene citrate possesses an FDA label warning regarding prolonged usage increasing the risk of borderline or invasive ovarian tumor development. Though no direct study comparing the risk of clomiphene citrate and BRCA1/2 germline variants exists, epidemiologic studies support these findings in the general population. Because BRCA1/2 carriers already possess an underlying risk for ovarian cancer, use of clomiphene citrate in these patients must be carefully monitored and considered on a patient-by-patient basis (FDA, 2012; Reigstad et al., 2017).

In order to reduce the risk of breast and ovarian cancer, BRCA1/2 germline carriers are encouraged to undergo risk-reducing bilateral salpingo-oophorectomy (rrBSO) upon completion of childbearing, leading to the induction of surgical menopause. Following surgery patients may experience postmenopausal symptoms, an indication for hormone replacement therapy. Studies have revealed that BRCA1/2 carriers possess no change or an even further decrease in breast cancer risk while using short-term HRT to control symptoms following surgical menopause (Eisen et al., 2008; Domchek et al., 2011; Kotsopoulos et al., 2016; Gordhandas et al., 2019). In summary, HRT remains contraindicated prior to prophylactic rrBSO in BRCA1/2 carriers due to an increased breast cancer risk. Following prophylactic rrBSO, short term use of HRT is reasonable and has not been demonstrated to increase risk for breast cancer. Long term use of HRT following prophylactic rrBSO is not advised.

Great strides have been made in delineating the most effective treatment method for triple negative breast cancer, tumors which are estrogen receptor (ER), progesterone receptor (PR), and HER2 negative. Further investigation has also identified a key relationship for platinum-based chemotherapies in patients harboring BRCA1/2 germline variants who develop TNBC. Multiple clinical studies reveal improved sensitivity and pathologic complete response to neoadjuvant cisplatin or carboplatin (Silver et al., 2010; Byrski et al., 2014; Hahnen et al., 2017; Caramelo et al., 2019). Similarly, TNBC patients with BRCA1/2 germline variants experienced significantly improved response to carboplatin when compared to the standard of care docetaxel treatment regimen (Tutt et al., 2018). The use of platinum-based agents provides patients with BRCA1/2 germline variants with triple negative breast cancer new avenues for future treatment regimens.

This class of medications is currently FDA approved for advanced, previously treated ovarian cancer with germline BRCA1/2 variants and previously treated metastatic HER2-negative BRCA1/2 variant breast cancer. Additionally, olaparib possesses approval for first-line maintenance therapy in BRCA variant ovarian cancer as well as approval for maintenance therapy of BRCA1/2 variant pancreatic cancer (Robson et al., 2017; Litton et al., 2018; FDA, 2020a; Madariaga et al., 2020). PARP enzymes are crucial in repair of single-stranded DNA breaks, thus inhibition of these enzymes allows these breaks to persist. BRCA1/2 carriers are incredibly sensitive to PARP-inhibitors, as single-strand breaks are coupled with the failed double-strand DNA repair leading to cell cycle arrest or cell death. (Farmer et al., 2005). Multiple clinical trials have investigated the efficacy of PARPi as monotherapy and in conjunction with other chemotherapies, with promising disease-free survival and progression free survival data (Madariaga et al., 2020). In a phase III trial, germline BRCA-variant pancreatic cancer patients who were treated with maintenance olaparib experienced prolonged progression-free survival compared to placebo (Golan et al., 2019). Promising safety and efficacy profiles have also been shown in rucaparib-based regimens for BRCA1/2 variant pancreatic cancer (Reiss et al., 2021). As clinical studies continue to delineate the role of PARPi in cancer therapy, this class of medications provides clinicians treating patients with germline BRCA1/2 variants a vast potential of clinical utility.

Programmed death ligand 1 (PD-L1) expression is currently the only FDA approved biomarker in advanced lung adenocarcinoma, acting as a prominent therapeutic target. STK11 variants have been shown to down regulate PD-L1 expression, rendering PD-1 axis inhibitors futile. Skoulidis et al. (2015) first identified STK11 tumor variants as a key initiator in resistance to PD-1 axis inhibitors while co-occurring with KRAS mutations. In follow-up to their findings, Skoulidis et al. (2018) formalized the specific role of STK11 in driving resistance in KRAS- mutated lung adenocarcinoma and hypothesized similar findings for STK11 variants regardless of KRAS status. Recent studies have expanded this hypothesis, as STK11 variants with wild-type KRAS also confer resistance (Laderian et al., 2020; Schoenfeld et al., 2020). Though further clinical investigation is needed, PD-1 axis inhibitors are likely to be less effective in patients possessing STK11 variants.

In 2018 Ulixertinib, a ERK1/2 inhibitor, was the first of its class to undergo Phase one study in MAPK mutant advanced solid tumors (Sullivan et al., 2018). This medication is highly potent and selective, resulting in reversible ATP-competitive inhibition of ERK one and 2. Using STK11 variant NSCLC cell lines and engineered mouse models, Caiola et al. (2020) found tumors with STK11 mutants expressed distinct sensitivity to ERK inhibitors. Though ERK inhibitors have yet to be studied clinically in patients with deleterious STK11 variants, these findings are encouraging for further investigation. ERK inhibitors may offer a promising therapeutic option for patients harboring STK11 variants in the future.

Evidence has shown increased levels of estrogen can contribute to lymphangioleiomyomatosis (LAM) induction or progression. Because individuals with pathogenic TSC1/2 variants have an increased baseline risk for LAM, it is advised that estrogen-containing products be limited or avoided in these patients (Yano, 2002; Oberstein et al., 2003). Though no direct clinical relationship has been defined between TSC variants and estrogen products, studies have revealed the promotion of invasiveness and survival of tuberin-null cells when treated with estrogens (Yu et al., 2004; Yu et al., 2009).

Kasper et al. (2018) identified both genotoxic chemotherapy agents (etoposide) and radiotherapy significantly increased the risk of tumor development in a Li-Fraumeni spectrum disease mice model. Their study also recognized that non-genotoxic agents such as docetaxel, a mitotic spindle poison, did not contribute to further tumor formation. In patients possessing a pathologic TP53 variant, it is advised that surgical and ablative therapies be given priority while avoiding radiotherapy and genotoxic chemotherapies when possible (Frebourg et al., 2020).

Multiple studies have identified TP53 mutations and 17p deletions as independent drivers of resistance to chemotherapeutic agents in CLL (Döhner et al., 1995; Hallek et al., 2010). Positive effective results were first observed in studies investigating the use of alemtuzumab (monoclonal antibody-CD52) in CLL patients with poor prognostic features including TP53 disruptions (Lozanski et al., 2004; Pettitt et al., 2012). This medication was approved as first line therapy for CLL before rebranding of the drug as a multiple sclerosis medication by the manufacturer led to the withdrawal of the license in 2012 (Hallek 2019; FDA, 2021). As a result, new and varied treatment regimens have been investigated with promising outcomes. CLL patients with TP53 dysfunction have seen much improved but not definitive disease control with small molecule agents such as venetoclax (BCL-2 inhibitor) and ibrutinib (Bruton tyrosine kinase inhibitor), especially when used in combination with rituximab and obinutuzumab or idelalisib (Farooqui et al., 2015; Roberts et al., 2016; Stilgenbauer et al., 2016; Hallek 2019). The use of chemotherapy agents as first line therapies in this patient group is not supported.

TP53 variants are negative prognostic indicators for clinical outcomes in patients with MCL (Eskelund et al., 2017). TP53 mutated MCL cells escape eradication by high dose cytarabine in combination with rituximab, a standard treatment for general MCL patients. Patients harboring germline TP53 mutations who develop MCL may be less likely to benefit from a cytarabine-rituximab combination therapy.

In a large cohort study of Chinese women with breast cancer, Sheng et al. (2020) identified patients possessing TP53 germline variants were more likely to respond to carboplatin-based (with or without anthracycline) neoadjuvant therapy compared to anthracycline or taxane-based regimens. Though future clinical studies are needed, these cohort findings represent a reasonable justification for choosing carboplatin-based therapy regimens in TP53-variant breast cancer.

5-FU is a synthetic pyrimidine antagonist included as first-line therapy in colorectal cancer regimens. Once transformed intracellularly, 5-FU metabolites disrupt RNA synthesis, initiate single and double-stranded breaks, and inhibit thymidylate synthase contributing to cellular apoptosis. As both germline and sporadic TP53 variants increase cellular ability to avoid apoptosis initiation, studies have identified TP53 null cells as resistant to 5-FU (Aghabozorgi et al., 2020). Patients with TP53 germline variants who develop colon cancer may be less likely to benefit from 5-FU based therapies.

Though patients with PTEN variants possess an increased risk for breast cancer development, there is no direct evidence to support the use of tamoxifen or raloxifene for breast cancer prevention. Additionally, women with PTEN germline mutations have up to 28% lifetime risk for endometrial cancer (Tischkowitz et al., 2020), for which these agents are known to increase the risk. Physicians may consider alternative agents in patients with PTEN variants in order to limit the potential increased risk of developing endometrial cancer (Yehia and Eng, 2001; Hobert and Eng, 2009).

Studies have identified PTEN protein function as a critical component in the therapeutic efficacy of trastuzumab. PTEN is necessary for rapid AKT-dephosphorylation by trastuzumab, contributing to its antiproliferative effect. Evidence also exists for a PTEN-related role in the mechanism of lapatinib, as PTEN knockout cell lines showed decreased sensitivity to clinically therapeutic levels of lapatinib (Nagata et al., 2004; Berns et al., 2007; Eichhorn et al., 2008; Wang et al., 2011). Future clinical studies investigating the efficacy of these agents in patients with PTEN variants are needed, though initial lab evidence indicates these agents may be less effective.

Currently used as part of the standard of care in estrogen receptor-positive HER2-negative advanced breast cancer, CDK4 and CDK6 inhibitors function by preventing complex formation with D-cyclins leading to tumor suppressor retinoblastoma protein (Rb) dephosphorylation and subsequent cell cycle arrest. Both in vitro and in vivo models of PTEN loss revealed increased levels of rephosphorylated Rb and cell cycle progression when treated with CDK4/6 inhibitors. Though the use of CDK4/6 inhibitors in patients with PTEN variants needs to be studied further in clinical trials, current evidence does not support successful use of these agents in this patient population (Costa et al., 2020).

Typically reserved for advanced breast cancer following CDK4/6 inhibitor resistance, PI3K-alpha inhibitors have been observed clinically and in cell line data to be ineffective when used in PTEN-null cells (Juric et al., 2015; Costa et al., 2020). Other agents may be more effective in patients with PTEN variants who develop advanced breast cancer.

Each of the described relationships above were identified in studies involving somatic/tumor driven PTEN variants and did not involve specific investigation of germline variants. Because breast cancer is one of the most common phenotypes in patients presenting with PHTS, we chose to include the discussions above. The in vitro and in vivo evidence supports the direct mechanistic link underlying how PTEN loss confers resistance to these drugs. Though future clinical evidence is needed relating specifically to germline variant patients, these medications may be less effective in PHTS patients.

Ubiquitously upregulated in VHL-variant tumors, HIF-2a is a key proximal signal stimulating tumor growth and has rapidly become a target of interest for potential systemic therapies for VHL patients. Pre-clinical and clinical studies have produced encouraging results, revealing safety and efficacy in patients with advanced clear cell renal cell carcinoma (Chen et al., 2016; Courtney et al., 2020; Choueiri et al., 2021). A phase II study was recently published investigating the objective response of VHL patients with renal cell carcinoma to belzutifan (MK-6482) treatment regimen. Jonasch et al. (2021) reported an objective partial response in 49% of patients, with an additional 49% of patients with stable disease. 96% of all patients experienced progression-free survival at 24 months. Remarkably, the study also reports partial or complete responses in additional VHL-associated neoplasms present within the study population. 77% of patients with pancreatic lesions, 91% of patients with pancreatic neuroendocrine tumors, and 30% of patients with central nervous system hemangioblastomas experienced a response following treatment with belzutifan. Additionally, all retinal hemangioblastomas present in the study population were graded as showing improvement. With only grade I and II adverse events reported, belzutifan has the ability to transform care for VHL patients providing a potential treatment option beyond surgical excision. This systemic therapy targets the underlying pathophysiology of the disease and thus far has shown to effectively halt or reduce VHL-associated tumors throughout the body with minimal side effects.

Fry et al. (2008) demonstrated that MUTYH knockout cells were less responsive upon exposure to a DNA alkylating agent. Due to MUTYH role in DNA base repair, alkylating agents are unable to successfully confer cytotoxicity through the formation of DNA crosslinks, escaping cell death. Though typically reserved for use in salvage regimens, alkylating agents play an important role in the treatment of ovarian cancer (Hutchcraft et al., 2021). Further study is necessary to determine whether individuals with ovarian cancer and biallelic germline pathologic variants in MUTYH demonstrate this potential resistance to alkylating agents.

Used to improve glycemic control in patients with type II diabetes mellitus, glucagon-like peptide 1 (GLP-1) agonists possess a black-box warning for risk of causing thyroid C-cell tumors. Though the clinical effects in humans are unknown, C-cell tumors developed in dose-dependent and duration-dependent manner in both genders of mice and rats but not primates (Bjerre Knudsen et al., 2010). This class of medications is contraindicated in patients with a personal or family history of MTC or MEN2 syndromes (FDA, 2010). Though studies document a GLP-1 receptor dependent role in C-cell hyperplasia and no association with RET activation, the FDA label remains (Madsen et al., 2012).

In 2011, the FDA approved the multi-target TKI vandetanib for symptomatic or progressive MTC with unresectable locally advanced or metastatic disease. The phase III study, which showed an objective response in 46.4% of hereditary RET-variant MTC, was the beginning of a cascade of investigation into this class of medications (Wells et al., 2012; FDA, 2014). Similarly cabozantinib, also a multi-target TKI, was approved by the FDA for the treatment of progressive, metastatic MTC (Elisei et al., 2013; FDA, 2014). A phase II study involving the use of sunitinib in the treatment of advanced/metastatic paraganglioma and pheochromocytoma found one patient with MEN2A and a germline RET variant experienced a 64% tumor volume reduction (O'Kane et al., 2019). Follow up studies involving these and other multi-target TKIs (sunitinib, sorafenib, lenvatinib, anlotinib) have produced a common negative trend, as many of these medications increase progression-free survival without reduction in tumor size and many patients go on to develop disease resistance over time while experiencing a myriad of toxicities (Okafor et al., 2021). As a result, the development and evaluation of highly selective RET-specific TKIs (selpercatinib and pralsetinib) are on the forefront of clinical investigation and are showing promise in preliminary studies. In their phase I/II study, Wirth et al. (2020) revealed a 69% response rate in patients with RET-variant MTC who had undergone prior treatment with vandetanib or cabozantinib and a 73% response rate in patients with no prior TKI therapy history when treated with selpercatinib. Subbian et al. (2021) reported similar findings for RET-variant MTC patients using a pralsetinib treatment regimen, as 60% of formerly treated patients experienced a response and 71% of patients without prior treatment experienced a response. Both drugs possess a much more tolerable side effect profile than the multi-target TKIs as a result of their specificity. Though isolated reports of acquired tumor resistance drive concerns regarding the long-term efficacy of RET-selective agents, future follow-up studies will be needed to evaluate the viability of prolonged treatment courses. RET-selective TKIs offer patients harboring RET-variant related disease a much needed option for systemic therapy, providing both substantial tumor responses and a tolerable toxicity profile.

Used in the management of metastatic paragangliomas and pheochromocytomas, evidence has shown patients with SDHB variants respond remarkably well to temozolomide-based regimens (Hadoux et al., 2014). Recent studies in SDHB-knockout mouse models showed improved cytotoxicity, reduced metastatic lesions, and prolonged overall survival when treated with temozolomide coupled with a PARP-inhibitor (Pang et al., 2018). The use of temozolomide should be highly considered in patients with SDHB variants who develop metastatic paragangliomas and pheochromocytomas.

TKIs can effectively treat KIT or PDGFRA mutated gastrointestinal stromal tumors (GISTs). However, SDHx-deficient GISTs display a poor response when treated with imatinib and limited response when treated with sunitinib (Boikos et al., 2016). There has been minimal investigation into alternative TKIs (Ibrahim and Chopra, 2020). Though these tumors possess a low overall mortality, SDHx-deficient GISTs are prone to progress and recur (Weldon et al., 2017). On the other end of the spectrum, case reports have shown quality responses in SDHx-null renal cell carcinoma to sunitinib and pazopanib (Paik et al., 2014; Shuch et al., 2016). Similarly, the role of TKIs in the treatment of advanced/metastatic paraganglioma and pheochromocytoma is encouraging, with evidence of a patient harboring an SDHB variant responding to sunitinib-based therapy (O'Kane et al., 2019). While further studies are needed to support the findings in both disease states, TKIs offer patients with SDHx-variant RCC or paraganglioma/pheochromocytoma a potential future therapeutic option when few others exist.

Because of the small sample size most of these studies generalize findings to include all SDHx variants. Specifically, Boikos study included SDHB and SDHA, Shuch included SDHC, Paik studied SHDB, and O’Kane reviewed SDHB and SDHA.

First recognized as a poor prognostic factor in colorectal cancer, more recent studies have identified a correlation between SMAD4 expression and 5-FU sensitivity. In patients with colorectal cancer treated with 5-FU, those with SMAD4 loss displayed a significant decrease in both overall survival and progression free survival (Alhopuro et al., 2005; Papageorgis et al., 2011; Wasserman et al., 2019). For patients harboring SMAD4 variants and requiring adjuvant chemotherapy, options other than 5-FU may likely be more effective.

Multiple studies have established an association between SMAD4 protein expression and sensitivity to cetuximab therapy. Lin et al. (2019) showed SMAD4 knockdown tumor cell lines were more viable and inhibited cell apoptosis when treated with cetuximab in comparison to cells with overexpression of SMAD4. Similar findings were observed in somatic SMAD4 loss of head and neck squamous cell carcinoma, conferring resistance to cetuximab therapy (Ozawa et al., 2017). Other agents are likely to be more successful than cetuximab in treating germline SMAD4 variant pathologies.

Wong et al. (2020), while also conferring resistance of SMAD4-negative cell lines to 5-FU, found these same lines also conferred resistance to irinotecan. Conversely, the study found no resistance to therapeutic oxaliplatin levels. Patients with colorectal cancer harboring SMAD4 pathogenic variants may obtain more benefit from adjuvant chemotherapies that do not include irinotecan.

Patients harboring SMAD4 variants are known to possess an increased risk for collagen-associated disorders, including aortic aneurysm or aortic dissection (Meng et al., 2019; Yu et al., 2019). Though no direct relationship has been established between fluoroquinolones and SMAD4 pathogenic variants, both are associated with an increased risk for aortic aneurysms and dissections. Because patients with pathogenic SMAD4 variants commonly have one or more features of hereditary hemorrhagic telangiectasia (HHT), these patients may potentially increase their risk for developing severe aortic symptoms when taking fluoroquinolones.

Fedier et al. (2001) found MLH1 and MSH2- deficient cell lines conferred resistance to topoisomerase II inhibitors (epirubicin, doxorubicin, and mitoxantrone). MLH1 loss has also been demonstrated to display resistance to topoisomerase I poisons. Etoposide resistance was also identified in previous studies in using MLH1 and MSH2 deficient colorectal and endometrial carcinoma cell lines respectively (Aebi et al., 1997). For patients possessing germline MLH1 or MSH2, use of topoisomerase-blocking agents are less likely to produce cell death.

Binding to DNA and creating DNA adducts, platinum agents produce crosslinks disrupting the DNA helix. These agents rely on a proper functioning mismatch repair system to identify damaged DNA and induce apoptosis. Studies have documented the role of MLH1 and MSH2 loss in the development of cisplatin and carboplatin resistance in colorectal carcinoma, as well as PMS2 loss conferring low level cisplatin resistance (Aebi et al., 1997; Fink et al., 1997a; Fink et al., 1997b; Martin et al., 2008). Similar resistance to cisplatin was also found in MLH1-silenced endometrial cell lines and MSH2-silenced bladder cancer cell lines (Li et al., 2018; Goodspeed et al., 2019). On the other hand, evidence has shown colorectal cancer cells possessing disrupted MLH1 and MSH6 confer similar sensitivity to oxaliplatin as wild-type cells (Fink et al., 1997a; Vaisman et al., 1998). When initiating chemotherapy regimens that include platinum agents, patients harboring MLH1 and MSH2 variants may be more successful with oxaliplatin over cisplatin or carboplatin-based regimens.

Though not all studies agree, most clinical findings indicate MLH1 and MSH2 deficiencies contribute to poorer outcomes with 5-FU treatment for colorectal cancer (Ribic et al., 2003; Sargent et al., 2010). Similar findings have been reported in multiple cell line studies, supporting evidence of resistance to 5-FU (Carethers et al., 1999; Meyers et al., 2001). Typically used as the standard of care for stage II and III colorectal cancer, 5-FU based regimen may not be as effective in patients with MLH1 and MSH2 variants.

Multiple studies have evaluated and identified high degrees of resistance from MLH1, MSH2, and MSH6 deficient tumor cell lines to temozolomide (Friedman et al., 1997; Taverna et al., 2000; Nguyen et al., 2014). Evidence for other alkylating agents such as cyclophosphamide and busulfan have also been implicated, though results are not consistent. Though further studies are needed to specifically address the role of these agents in patients with germline variants, the aforementioned studies present evidence of resistance in patient tumor samples indicating that these agents may be less likely to be effective.

Like FAP patients, Lynch Syndrome patients have also seen quality outcomes when treated with aspirin and NSAIDs. In a long-term follow-up to their 2011 CAPP2 study, Burn et al. (2020) showed that aspirin provides significant protective effects against colorectal cancer in Lynch Syndrome patients for an upwards of 20 years. Daily aspirin use for at least 2 years produced a reduced hazard ratio of 0.65 and 0.56 for intention-to-treat and per-protocol analysis, respectively. Ouakrim et al. (2015) produced related results when investigating both aspirin and ibuprofen. In their study, Lynch Syndrome patients treated with aspirin for 1 month were estimated to experience a 60% decrease in colon cancer risk and a 65% decrease in risk when treated with 1 month of ibuprofen. A recent phase I study found naproxen was safe for chronic use as a primary and secondary chemopreventative intervention at both low and high doses in Lynch syndrome patients. Additionally, a co-occurring tissue-specific mouse model showed naproxen modulated tumor growth and prolonged survival (Reyes-Uribe et al., 2021). Currently underway are two additional randomized clinical trials, CAPP3 and AAS-Lynch, which share a primary endpoint of comparing the effectiveness of varying aspirin doses in preventing colorectal cancer in Lynch Syndrome patients (Soualy et al., 2020).