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Thymidylate synthase (TS) is a critical rate-limiting enzyme of DNA synthesis. Patients with high levels of this gene in their tumors tend to respond less favorably to drug combinations that include TS inhibitors such as 5-FU. The higher response rate of adenocarcinoma of the lung to TS-directed agents compared to squamous cell lung cancer has been ascribed to lower median TS expression in the adenocarcinoma histology.1, 2, 3 A recent clinical trial showed that lower TS expression was associated with better response of NSCLC to neoadjuvant chemotherapy with gemcitabine and pemetrexed.3
1. Ceppi et al. 2006. Cancer 107:1589–96.
2. Ishihama et al. 2009. Jpn J Clin Oncol 39:33–6.
3. Scagliotti et al. 2008. J Clin Oncol 26:3543–3551.
The enzyme excision repair complementing factor 1 (ERCC1) is part of the pathway that repairs DNA damage caused by platinum-based therapy. Low ERCC1 has consistently been found in several retrospective studies to be a favorable indicator for response of tumors and/or improved survival of lung cancer patients after platinum therapy, while high ERCC1 expression was predictive of resistance to platinum therapy and shorter survival.1, 2, 3 In a prospective trial of 366 lung cancer patients, those with low ERCC1 were selected for platin-based therapy while those with high ERCC1 expression were directed to alternate non-platin therapy. The result was a significantly higher overall response rate in the selected groups (the “genotypic arm”) than in the non-selected control arm.4 A prospective phase II feasibility trial in which patients’ therapy was chosen based on their ERCC1 expression showed much higher response rates than historical ones.5 The results of both of the above studies suggest that high ERCC1 patients treated with non-platinum therapy may also achieve a better result than that seen in non-selected groups of patients.
1. Ceppi et al. 2006. Annals of Oncology 17:1818–25.
2. Lord et al. 2002. Clin Cancer Res 8:2286–91.
3. Lee et al. 2008. Lung Cancer 59:95–104.
4. Cobo et al. 2007. J Clin Oncol 25:2747–54.
5. Simon et al. 2007. J Clin Oncol 25:2741–6.
The epidermal growth factor receptor (EGFR; ErbB-1; HER1) is a critical part of the signal transduction pathway that controls cell growth and is often over-expressed (amplified) in tumors. A higher number of gene copies has been shown to correlate with increased response of non-small cell lung cancer (NSCLC) to the EGFR-directed small-molecule TKI’s.1, 2, 3
1. Cappuzzo et al. 2005. J Natl Cancer Inst 97:643–55.
2. Cappuzzo et al. 2007. J Clin Oncol 25:2248–5.
3. Tsao et al. 2005. N Engl J Med 353:133–44.
RRM1 is the active subunit of ribonucleotide reductase (RR), which is a key enzyme involved in DNA synthesis. Gemcitabine interferes with the function of RRM1, thus reducing the pool of deoxyribonucleotides available for DNA synthesis. Low levels of RRM1 gene expression have been associated with increased survival to gemcitabine/platin therapy in NSCLC.1, 2, 3 A prospectively analyzed clinical trial of NSCLC patients treated with gemcitabine and carboplatin showed that lower levels of RRM1 correlated significantly with tumor response.4 A recent feasibility trial was performed in which therapies were assigned taking into account both RRM1 and ERCC1 gene expressions.5 Patients with low RRM1 were given either gemcitabine/carboplatin if their ERCC1 levels were low, or gemcitabine/docetaxel if their ERCC1 levels were high; patients with high RRM1 were given docetaxel/carboplatin if they had low ERCC1 and docetaxel/vinorelbine if they had high ERCC1. All four selected arms showed response rates of around 44%, compared to about 25% in historical controls of unselected patients.5
1. Rosell et al. 2003. Oncogene 22:3548–53.
2. Rosell et al. 2003. Clin Cancer Res 10:1318–25.
3. Ceppi et al. 2006. Ann Oncol 17:1818–25.
4. Bepler et al. 2006. J Clin Oncol 24:4731–37.
5. Simon et al. 2007. J Clin Oncol 25:2741–6.
The epidermal growth factor receptor (EGFR; ErbB-1; HER1) is a critical part of the signal transduction pathway that controls cell growth and differentiation. Mutations in EGFR appear in about 13-16% of NSCLC patients.1, 2, 3 An earlier study showed that 90% of patients responding to TKIs had EGFR mutations, while non-responding patients did not.1 In the phase III TRIBUTE trial, patients were treated with chemotherapy that included erlotinib along with carboplatin and paclitaxel.2 Those with EGFR mutations had a 53% response rate compared to 18% who did not, and a significantly longer median survival was seen for the EGFR-mutated patients.2 A recent prospective trial showed a 70% response rate to TKI therapy among patients who had the E19del and L858R mutations in their EGFR genes.3
1. Lynch et al. 2004. New Engl J Med 350:2129–39.
2. Eberhard et al. 2005. J Clin Oncol 23:5900–09.
3. Rosell et al. 2009. N Engl J Med. 361:958–67.
The echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion gene can be detected in subsets of NSCLC,1 almost entirely in adenocarcinoma, and appears to be mutually exclusive of EGFR and KRAS mutations.1, 2 Patients who harbor this mutation do not benefit from EGFR TKIs.3 Recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harboring EML4-ALK translocations.4 RGI has designed a PCR-based assay that can detect and identify 9 known EML4-ALK fusion mutations and is suitable for use with FFPE tissues.
1. Soda et al. 2007. Nature 448:561–6.
2. Inamura et al. 2008. J Thorac Oncol 3:13–7.
3. Shaw et al. 2009. J Clin Oncol 27:4247–4253.
4. Saski et al. 2010. Eur J Cancer Apr 23.
KRAS, a vital member of the signal transduction pathways that regulate cell growth, is mutated in about 30% of lung cancers.1 KRAS mutations have previously been associated with almost complete resistance to EGFR-directed drugs used in NSCLC therapy. In four independent clinical correlative studies involving 134 NSCLC patients, those with KRAS-mutants showed poorer clinical outcomes to treatment with EGFR-directed TKI’s, either in terms of no response or no survival benefit1, 2, 3, 4 while in the Canadian BR.21 trial of erlotinib vs. placebo, only one response was noted among 30 KRAS mutant patients.5 However, several recent studies have not found a clear predictive role for KRAS mutations for either erlotinib or cetuximab therapy in NSCLC.6, 7
1. Pao et al. 2005. PLoS Medicine 2:e17.
2. Massarelli et al. 2007. Clin Cancer Res 13:2890–6.
3. Eberhard et al. 2005. J Clin Oncol 23:5900–9.
4. van Zandwijk et al. 2007. Ann Oncol 18:99–103.
5. Zhu et al. 2008. J Clin Oncol 26:4268–7.
6. Brugger et al. 2009. J Clin Oncol 27:15s (abs 8020).
7. Gandara et al. 2009. J Clin Oncol 27:15s (abs 8015).
The epidermal growth factor receptor (EGFR; ErbB-1; HER1) is a critical part of the signal transduction pathway that controls cell growth and is often over-expressed in tumors. In a study evaluating 8 different genes as predictive factors for first-line CPT-11-based chemotherapy in colorectal cancer patients, a high intratumoral gene expression levels of EGFR was shown to be the most important factor in distinguishing responders from non-responders.1
1. Vallbohmer et al. 2006. Int J Cancer 119:2435–2442.
The enzyme excision repair complementing factor 1 (ERCC1) is part of the pathway that repairs DNA damage caused by platin therapy. Low ERCC1 has consistently been found in several retrospective studies to be a favorable indicator for response of tumors and/or improved survival after platinum therapy while high ERCC1 expression is associated with resistance to platinum therapy and shorter survival in many cancer types including gastric, ovarian, bladder, head-and-neck, non-small cell lung, esophageal and colorectal. In a study of advanced colorectal cancer study treated with 5-FU/oxaliplatin,1 low ERCC1 mRNA expression levels were significantly associated with longer survival. In contrast to oxaliplatin regimens, high expression of ERCC1 was correlated with response to irinotecan therapy.2
1. Shirota et al. 2002. J Clin Oncol 19:4298–304.
2. Vallböhmer et al. 2006. Int J Cancer 119:2435–42.
Thymidylate synthase (TS) is a growth rate-limiting enzyme of DNA synthesis. TS expression is a predictor of response to 5-fluorouracil (5-FU), which for over 50 years has been a mainstay of chemotherapy of colorectal cancer (CRC). Many studies have agreed that high levels of TS are associated with resistance of tumors to 5-FU and its derivatives, even when used in combination with other agents such as oxaliplatin (the FOLFOX regimen).1, 2, 3, 4
1. Leichman et al. 1997. J Clin Oncol 15:3223–29.
3. Aschele et al. 1999. J Clin Oncol 17:1760–70.
4. Salonga et al. 2000. Clin Cancer Res 6:1322–27.
5. Johnston et al. 1995. Cancer Res 55:1407–12.
KRAS, a vital member of the signal transduction pathways that regulate cell growth, is often mutated in tumors. Mutations in KRAS gene preclude response to EGFR-directed tyrosine kinase inhibitors (TKI) but not all tumors with wild-type KRAS will respond either. A recent study showed that a V600E mutation in BRAF, a gene that is downstream of KRAS in same cell cycle signaling pathway, identified a further set of 12-15% of metastatic colorectal cancer patients with wild-type KRAS who would fail to respond to TKI’s.1 Both a wild-type BRAF gene as well as a wild-type KRAS gene are necessary for response.
1. Nicolantonio et al. 2008. J Clin Oncol 26:5705–12.
KRAS, a vital member of the signal transduction pathways that regulate cell growth, is often mutated in tumors. The presence of KRAS mutations, which occur predominantly in patients who are current or past smokers, is strongly associated with a lack of response of CRC to the anti-EGFR antibody cetuximab. Three independent studies reported response rates of 0% to cetuximab among patients with mutated KRAS as well as shorter overall survival.1, 2, 3
1. Lièvre et al. 2008. J Clin Oncol 26:374–9.
2. De Roock et al. 2008. Ann Oncol 19:508–15.
3. Di Fiore et al. 2007. Br J Cancer 96:1166–9.
Thymidylate synthase (TS) is a critical rate-limiting enzyme of DNA synthesis. It has been shown that TS gene expression (TS mRNA level) within primary adenocarcinoma of the stomach has an inverse relationship to response and survival for patients who receive fluorouracil (5-FU)-based chemotherapy.1 In this study, chemotherapy consisted of two cycles of 5-FU/cisplatin. The median survival time was 43+ months for treated patients with TS mRNA expression levels less than the median and 6 months for those with TS mRNA levels greater than the median. The conclusion of this study was that the gene expression of TS influences response to 5-FU-based chemotherapy and survival for a cohort of patients with primary gastric cancer.1
1. Lenz et al. 1996. J Clin Oncol 14:176–82.
The enzyme excision repair complementing factor 1 (ERCC1) is part of the pathway that repairs DNA damage caused by platin-based therapy. Studies have consistently found ERCC1 expression to be associated with tumor response and/or survival after platinum-based therapy in many different cancer types. In one study, gastric cancer patients treated with 5-FU/leucovorin/cisplatin by infusion, the median survival for patients above the median ERCC1 gene expression was 5.4 months, whereas for those below the median the median survival had not been reached at the time this study was published.1 Moreover, the median TS mRNA level also segregated responsive and drug-resistant tumors. Another study showed that after treatment with a modified FOLFOX (5-FU/leucovorin/oxaliplatin) regimen, patients with low ERCC1 levels had a median survival time significantly longer than those with high levels,2 corresponding to a hazard ratio of 9.4 for the high ERCC1 expressing patients. In patients given first-line cisplatin-based regimens, low ERCC1 correlated with a higher response rate (low: 55.6% vs high:18.8%).3
1. Metzger et al. 1998. J Clin Oncol 16:309–16.
2. Wei et al. 2008. Br J Cancer 98:1398–402.
3. Matsubara et al. 2008. Br J Cancer. 98:832–9.
HER2 (also known as ErbB-2 ) stands for HumanEpidermalgrowthfactorReceptor2 and is part of a signal transduction pathway regulating cell growth and differentiation. Over-expression of HER2 has been associated with increased disease recurrence and worse prognosis in breast cancers. HER2-positive breast cancer is often treated with trastuzumab (Herceptin), a monoclonal antibody that blocks HER2 receptors. A recent clinical trial (the ToGA study) was the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of Herceptin in HER2-positive gastric cancer. Median overall survival (OS) was significantly improved with Herceptin+chemotherapy (CT) compared to CT alone.1 While HER2 positivity has historically been assessed by fluorescence in situ hybridization (FISH) to determine the degree of gene amplification, recent studies have shown a high degree of concordance between RT-PCR assessment and FISH assessment of gene amplification.2, 3 Using a HER2 gene expression cut-off value of 0.55, RGI has found that > 95% of FISH-positive tumors can be identified by PCR.2
1. Van Cutsem et al. 2009. J Clin Oncol 27:18s, 2009 (abs 4509).
2. Press et al. 2008. Clin Cancer Res 14:7861–9.
3. Baehner et al. 2008. 2008 ASCO Breast Cancer Symposium Abstract 41.