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Reliable TNM classification is mandatory in order to advise colorectal cancer patients regarding prognosis and optimal choice of treatment strategy. Despite the ...
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BRAF refines clinical interpretation of mismatch repair deficiency in colorectal cancer

“We are not likely to see any large randomized studies giving absolute evidence that mismatch repair and BRAF immunohistochemistry will improve survival and be cost effective, but we can choose a scientific approach based on biology and the key clinical data…” Lars Henrik Jensen* Reliable TNM classification is mandatory in order to advise colorectal cancer patients regarding prognosis and optimal choice of treatment strategy. Despite the revolution in molecular biology, molecular markers have had a minor role in the initial characterization of colorectal cancer. It is now time to not only use immunohistochemical ana­lysis of the mismatch repair (MMR) system, but also BRAF as the standard screening strategy in every new colorectal cancer. It is well known that the MMR system is clinically relevant for prognosis, heredity and treatment choices, but it is now becoming clearer that knowledge of BRAF status further supports all of these important questions. Other prerequisites for carrying out BRAF testing in the daily clinic – availability, fair price and reliability – have also been sufficiently satisfied. BRAF BRAF is a proto-oncogene in the RAS– RAF–MEK–ERK–MAP kinase pathway that affects cell division, differentiation and secretion. A missense mutation (V600E) in

the kinase domain activates the serine/threonine kinase and causes RAS‑independent downstream signaling [1]. Until recently, the BRAF V600E mutation could only reliably be analyzed using gene sequencing. Therefore, ana­ lysis has been restricted to molecular biology laboratories and academic-based clinical departments of pathology. A new mutation-specific immunohistochemical approach has now been validated against sequencing [2] and tested in several settings with promising results [3,4]. Mismatch repair There are four important proteins involved in DNA MMRs: MLH1, PMS2, MSH2 and MSH6. They work in pairs detecting and correcting base-to-base mispairing and loop formation. The system dysfunctions in Lynch syndrome, which is caused by hereditary mutations in any of the four genes. MLH1 and MSH2 mutations are the commonest, while MSH6 and especially PMS2 mutations are rare [5]. The only known somatic (i.e., nonhereditary)

“A new mutation-specific immunohistochemical approach has now been validated against sequencing and tested in several settings with promising results.”

*Department of Oncology, Vejle Hospital, DK-7100 Vejle, Denmark; Tel.: +45 79406802/+45 79406000; Fax: +45 79406907; [email protected]

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EDITORIAL Jensen cause of MMR deficiency (dMMR) is MLH1 promoter hypermethylation [6]. Immunohistochemistry is a reliable way to detect dMMR and is a standard ana­lysis in most pathology departments [7]. The advantages of this test are the positive internal control from protein expression in non-neoplastic cells, the fast procedure, low cost and information gained about the affected gene. PMS2 and MSH6 are lost in the absence of MLH1 and MSH2, respectively, while isolated loss of PMS2 or MSH6 is typical for a mutation in the corresponding gene. dMMR causes accumulation of length mutations in tumor DNA compared with normal DNA. This is detected as microsatellite instability [5]. Prognosis It is well known that dMMR is a positive prognostic factor [8] and it has also been suggested as a marker for deselecting stage II patients for adjuvant chemotherapy [101]. More data are now accumulating, indicating that BRAF holds additional prognostic information. In a recent study, patients with proficient MMR (pMMR)/BRAF mutant tumors had a worse outcome, while dMMR/BRAF mutant and especially dMMR/BRAF wild-type patients had a favorable outcome. Toon and colleagues conclude that combined BRAF and MMR status is a marker for prognostic risk stratification [9].

“It would be of major

clinical interest if a negative prognosis can be repealed by a positive predictive value for a certain treatment.”

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Heredity It can be extracted from the description of MMR above that immunohistochemistry can readily detect tumors probably caused by hereditary mutations in MSH2, MSH6 or PMS2. In the case of MLH1 deficiency, the sporadic pheno­ menon promoter hypermethylation is seen in nine out of ten tumors. Methylation ana­lysis is available in specialized laboratories and it makes good sense to perform it in order to identify the vast majority of dMMR patients with sporadic disease. Interestingly, BRAF V600E is a carcinogenic mutation not seen in Lynch syndrome [10]. It is, therefore, an alternative to MLH1 promoter methylation in the identification of sporadic MLH1-negative cases. Some laboratories have found BRAF sequencing easier than methylation assays and its clinical value has been validated [11]. As mentioned above, immunohistochemical detection of BR AF mutations is now available and can be performed by the pathologist together with MMR. This is a major step forward in the so-called

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reflex screening for Lynch syndrome. Every new colorectal cancer should be characterized with respect to MMR and BRAF. In dMMR cases without BRAF mutations, the patient should be offered genetic counselling. Approximately 2–4% of all colorectal cancers can be identified by this method and each proband will have, on average, three family members with the same mutation [12]. With regular colonoscopies and endometrial ultrasound, cancer deaths can be prevented. Treatment „„ Surgery

If immunohistochemistry for MMR and BRAF mutations are performed at the time of diagnosis on the diagnostic biopsies [13], Lynch syndrome can be detected before surgery. This allows the surgeon to take the high risk of new cancers into account and the patient may be advised to have a total or subtotal colectomy [7]. Therefore, clinical geneticists should participate in the multidisciplinary assessment of all colorectal cancer patients to allow timely counseling. „„ Adjuvant chemotherapy

MMR and BRAF status identify subgroups where the favourable prognosis does not justify adjuvant chemotherapy and a subgroup of pMMR/BRAF mutations with a high risk of relapse and, thus, a strong indication for adjuvant chemotherapy. This should be discussed with the patient. Prognostic markers identify patients at risk of relapse, while predictive markers identify treatments likely to kill tumor cells irrespective of the risk of relapse. The predictive effect of dMMR has been a matter of great debate and conflicting results. A common interpretation is that dMMR tumors are less sensitive to adjuvant monotherapy with 5‑fluorouracil and it should be avoided [14]. The standard of care is 5‑fluorouracil and oxaliplatin, and it should be offered to patients eligible for combination chemotherapy. Another interpretation is that a positive effect of chemotherapy in dMMR patients might be driven by the subgroup of patients with hereditary disease and not sporadic dMMR [15], rendering wildtype BRAF as a marker of sporadicity even more important. „„ Chemotherapy for metastatic disease

In metastatic colorectal cancer, MMR status does not seem to be a predictor of the effectiveness of

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BRAF refines clinical interpretation of mismatch repair deficiency in colorectal cancer  available systemic therapies. BRAF V600E on the other hand is very important. BRAF and RAS mutations are mutually exclusive and are downstream of EGFR. In theory, this renders the tumor insensitive to extra­cellular blockage with the EGFR inhibitors cetuximab and panitumumab. In practice, tumors harboring the BRAF V600E do not respond to these drugs. There may be a small effect in terms of progression-free survival and overall survival [16], but the potential minor benefit does not justify the use of EGFR inhibitors. The study also confirmed that patients with BRAF V600E have a very bad outcome in the metastatic setting, with survival times halved. In early-phase trials, the selected subgroup of patients with the BRAF V600E mutation seemed to benefit from more intense chemotherapy with triplet cyto­toxics combined with bevacizumab [17]. It would be of major clinical interest if a negative prognosis can be repealed by a positive predictive value for a certain treatment. Conclusion In my opinion, immunohistochemistry for MLH1, PMS2, MSH2, MSH6 and BRAF should be performed in every new colorectal cancer, preferably on the diagnostic biopsies. Based on the results, the patients can be informed more precisely about prognosis, the treating doctors have a more solid background to suggest the optimal treatment, whether it is surgery, chemo­therapy or a combination, and the specific hereditary disease Lynch syndrome can be References 1

Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

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Sinicrope FA, Smyrk TC, Tougeron D et al. Mutation-specific antibody detects mutant BRAFV600E protein expression in human colon carcinomas. Cancer 119(15), 2765–2770 (2013).

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Capper D, Voigt A, Bozukova G et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int. J. Cancer 133(7), 1624–1630 (2013).

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Toon CW, Chou A, Desilva K et al. BRAF V600E immunohistochemistry in conjunction with mismatch repair status predicts survival in patients with colorectal cancer. Mod. Pathol.

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identified with the potential to prevent cancer death in the patient and their family. Future perspective We are not likely to see any large randomized studies giving absolute evidence that MMR and BRAF immunohistochemistry will improve survival and be cost effective, but we can choose a scientific approach based on biology and the key clinical data highlighted above. Immunohistochemical data should be collected in comprehensive databases and, thus, allow comparative effectiveness research of BRAF in clinics. Other research areas include BRAF as a marker for effect of adjuvant chemotherapy and, in the metastatic setting, randomized trials should confirm the benefit from intense first-line chemotherapy in metastatic BRAF-mutated cases. With the implementation of BRAF ana­lysis as an integrated part of reflex screening for Lynch syndrome, a basis is founded for cost–benefit analyses, general adoption and lives being saved.

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“In my opinion, immunohistochemistry for MLH1, PMS2, MSH2, MSH6 and BRAF should be performed in every new colorectal cancer, preferably on the diagnostic biopsies.”

Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

doi:10.1038/modpathol.2013.200 (2013) (Epub ahead of print). 5

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Hendriks YMC, de Jong AE, Morreau H et al. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J. Clin. 56(4), 213–225 (2006). Wheeler JM, Loukola A, Aaltonen LA, Mortensen NJ, Bodmer WF. The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers. J. Med. Genet. 37(8), 588–592 (2000). Vasen HFA, Blanco I, Aktan-Collan K et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62(6), 812–823 (2013).

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Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23(3), 609–618 (2005).

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Toon CW, Walsh MD, Chou A et al. BRAF V600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am. J. Surg. Pathol. 37, 1592–1602 (2013).

10 Domingo E, Laiho P, Ollikainen M et al.

BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J. Med. Genet. 41(9), 664–668 (2004). 11 Jensen LH, Lindebjerg J, Byriel L, Kolvraa S,

Crüger DG. Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. Colorectal Dis. 10(5), 490–497 (2008).

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EDITORIAL Jensen 12 Hampel H, Frankel WL, Martin E et al.

Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J. Clin. Oncol. 26(35), 5783–5788 (2008). 13 Shia J, Stadler Z, Weiser MR et al.

Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples? Am. J. Surg. Pathol. 35(3), 447–454 (2011). 14 Sargent DJ, Marsoni S, Monges G et al.

Defective mismatch repair as a predictive marker for lack of efficacy of

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fluorouracil‑based adjuvant therapy in colon cancer. J. Clin. Oncol. 28(20), 3219–3226 (2010). 15 Sinicrope FA, Foster NR, Thibodeau SN et al.

DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J. Natl. Cancer Inst. 103(11), 863–875 (2011). 16 Douillard J-Y, Oliner KS, Siena S et al.

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369(11), 1023–1034 (2013).

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17 Loupakis F, Cremolini C, Salvatore L et al.

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur. J. Cancer doi:10.1016/j. ejca.2013.08.024 (2013) (Epub ahead of print). „„ Website 101 NCCN Guidelines Version 3. 2012. Colon

Cancer (2012). www.nccn.org/professionals/physician_gls/ pdf/colon.pdf

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