SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). XALKORI® (Crizotinib) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In an open label phase III trial involving 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, treatment with XALKORI® significantly improved Progression Free Survival (PFS) and Response Rates (RR). In spite of this initial benefit, patients will however relapse within 12 months, with the average response duration of about 8 months. This has been attributed to acquired mutation within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, subtherapeutic inhibition of ALK tyrosine kinase or activation of other pathways that can cause abnormal cell proliferation. Ceritinib (LDK378) is an oral, small molecule, second generation tyrosine kinase inhibitor of ALK and is 20 times as potent as XALKORI® against ALK. Unlike XALKORI®, Ceritinib does not inhibit MET kinase activity. Based on preclinical data supporting the efficacy of Ceritinib in both XALKORI® sensitive and resistant NSCLC tumors, the authors conducted a study to evaluate the antitumor activity of Ceritinib in patients with advanced NSCLC and other cancers harboring genetic alterations in ALK, in addition to determining the safety, MTD (maximum tolerated dose) and pharmacokinetics of Ceritinib. In this trial, patients who had received prior therapy with one or more ALK inhibitors as well as those with asymptomatic treated or untreated CNS metastases, were eligible to be enrolled. This study had 2 components – a dose escalation phase and an expansion phase. In the dose escalation phase, 59 patients were enrolled and the MTD of Ceritinib was determined to be 750 mg PO daily. In the expansion phase, 71 additional patients were treated for a total of 130 patients (N=59+71). Majority of these patients (94%) had advanced NSCLC. Patients with NSCLC who received at least 400mg of Ceritinib daily (N=114) had an overall response rate (RR) of 58% and median PFS was 7 months. Patients with advanced NSCLC who had received XALKORI® prior to enrollment (N=80) had a RR of 56%. The responses were noted both in patients with tumors harboring resistance mutations in the ALK tyrosine kinase domain as well as those in whom there was no new genetic alterations of ALK. Further, responses were seen in the untreated CNS lesions both in patients who had prior therapy with XALKORI® as well as those who did not. Adverse events were grade 1or 2 and GI related. These included vomiting, diarrhea, elevated aminotransferase levels and hypophosphatemia. The authors concluded that Cerifinib has marked antitumor activity in patients with advanced ALK rearranged NSCLC and in those who had progressed during XALKORI® treatment, regardless of the presence of resistance mutations in the ALK tyrosine kinase domain. Whether Cerifinib should be considered for the first line treatment of advanced ALK rearranged NSCLC, remains to be seen. Shaw AT, Kim D, Mehra R, et al. N Engl J Med 2014; 370:1189-1197
When any of these genes are mutated, repair of DNA replication mistakes is prevented resulting in continuous division of abnormal cells and possibly cancer. The EPCAM gene lies next to the MSH2 gene on chromosome 2 and mutations in the EPCAM gene can cause the MSH2 gene to be inactivated, interrupting DNA repair and leading to accumulation of DNA replication errors and possible malignancy. A Clinical Diagnosis of Lynch Syndrome can be made based on personal and family history if at least three relatives have a malignancy associated with Lynch Syndrome such as colorectal, endometrial, small bowel, ureter or renal pelvis cancer. In addition the following criteria should be met: • One relative must be a first-degree relative of the other two. • At least two successive generations must be affected. • At least one relative with a Lynch syndrome associated cancer should be diagnosed before 50 years of age. • Familial Adenomatous Polyposis should be excluded. • Tumors should be verified whenever possible. Because family history can sometimes be difficult to obtain or confirm NCCN in those circumstances has recommended screening all newly diagnosed colorectal cancer patients for Lynch syndrome. Germline defects/mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2 results in microsatellite instability in tumors. Tumors are described as MSI-High when they have changes in 2 or more, of the 5 microsatellite markers. So, High levels of MSI within a tumor are suggestive of defective DNA mismatch repair. ImmunoHistoChemistry (IHC) staining of tumor tissue is performed for protein expression of the four mismatch repair genes known to be mutated in Lynch Syndrome (MLH1, MSH2, MSH6 and PMS2). IHC test is described as normal when all 4 mismatch repair proteins are normally expressed suggesting that an underlying mismatch repair gene mutation is unlikely. When IHC test is abnormal, it means that that at least one of the 4 mismatch repair proteins is not expressed and an inherited mutation may be present in the gene related to that protein. This can be further confirmed by mutation analysis of the corresponding gene. Screening tests for Lynch syndrome include IHC staining of tumor tissue for protein expression of the four mismatch repair genes and tumor evaluation for MSI. In LS, more than 90% of the tumors are MSI-H (microsatellite instability-high) and/or lack expression of at least one of the mismatch repair proteins by IHC staining and there is a 96% correlation between IHC and MSI when used as a screening test for LS. Approximately 5% of tumors that display MSI may have normal protein expression for the four mismatch repair genes. It should be noted that an abnormal MSI and/or IHC test in colon cancer patients is not diagnostic of Lynch syndrome but can be a useful screening test. This is because even though MSI in the tumor tissue is pathognomonic of Lynch syndrome, approximately 15% of patients with sporadic colorectal cancers exhibit tumors with high MSI as a result of somatic MLH1 promoter hypermethylation. Further, the majority of colon cancer tumors that lack protein expression on IHC staining of MLH1 (often coexisting with loss of PMS2) are often due to an acquired genetic defect. If the IHC indicates absence of MLH1 protein expression, tumor should be tested for BRAF mutation V600E which can be seen in sporadic colorectal cancers but rarely found in patients who have Lynch Syndrome. Once a diagnosis of Lynch Syndrome is made, at risk family members should undergo colonoscopic evaluation at 20-25 years of age or 2-5 years prior to the earliest colon cancer, if it is diagnosed before age 25 and is repeated every 1-2 years. Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) should be considered by women who have completed childbearing. NCCN Guidelines Version 1.2014 Lynch Syndrome
These proteins are transmembrane tyrosine kinases and are involved in normal cell growth and differentiation. HER1 is also known as Epidermal Growth Factor Receptor or EGFR. These receptors are activated following ligand binding, receptor pairing or dimerization and phosphorylation. This dimerization (receptor pairing) occurs often within the HER family of receptors. This has been no ligand identified for HER2 receptor, although it is able to form homo and heterodimers with other members of the HER family readily. Dimerization of HER2 and HER3 is believed to produce the strongest mitogenic signaling and activates two important pathways that regulate cell survival and growth – Mitogen Activated Protein Kinase (MAPK) pathway and PhosphoInositide 3-Kinase (PI3K) pathway. For this reason inhibiting HER2 dimerization appears to be an important step in the treatment of cancer. Overexpression of HER2 in breast cancer has been associated with higher risk for relapse as well as overall survival. Approximately 20 percent of breast cancers are HER2-positive. HERCEPTIN® is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. PERJETA® is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie. HER3, HER1 and HER4. Thus HERCEPTIN® along with PERJETA® provide a more comprehensive blockade of HER2 driven signaling pathways. The accelerated approval of PERJETA® for the neoadjuvant treatment of breast cancer was based on a randomized, multicenter, open-label, phase II trial, in which 417 patients with HER2-positive, operable, locally advanced or inflammatory breast cancer (T2-4d), were randomly assigned to receive preoperative therapy with either HERCEPTIN® plus TAXOTERE® (Docetaxel), PERJETA® plus HERCEPTIN® and TAXOTERE®, PERJETA® plus HERCEPTIN® or PERJETA® plus TAXOTERE®. Patients in the three drug group received preoperative therapy with PERJETA®, HERCEPTIN® and TAXOTERE® every 3 weeks for a total of 4 cycles and following surgery, all patients received 3 cycles of Fluorouracil, ELLENCE® (Epirubicin), and CYTOXAN® (Cyclophosphamide) – (FEC) IV every 3 weeks and HERCEPTIN® was continued every 3 weeks for a total of one year of therapy. The primary endpoint was pathological Complete Response (pCR) rate defined as the absence of invasive cancer in the breast. The FDA definition of pCR is the absence of invasive cancer in the breast and lymph nodes. All treatment groups were well balanced. Seven percent of patients had inflammatory breast cancer, 32% had locally advanced cancer and 70% had clinically node-positive breast cancer. Forty-seven percent of the patients had hormone receptor-positive disease. The FDA defined pCR rates were 39.3% in the PERJETA® plus HERCEPTIN® and TAXOTERE® group and 21.5% in the HERCEPTIN® plus TAXOTERE® group (P=0.0063). Of Interest, the pCR rates in the three drug group were lower in patients with hormone receptor positive tumors compared to patients with hormone receptor negative tumors. The most common adverse events in the three drug group were alopecia, diarrhea, nausea and neutropenia. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions and anaphylaxis. Based on clinical studies, for the neoadjuvant treatment of breast cancer, PERJETA® should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer. • Four preoperative cycles of PERJETA® in combination with HERCEPTIN® and TAXOTERE® followed by 3 postoperative cycles of Fluorouracil, ELLENCE® and CYTOXAN® (FEC). • Three preoperative cycles of FEC alone followed by 3 preoperative cycles of PERJETA® in combination with TAXOTERE® and HERCEPTIN®. • Six preoperative cycles of PERJETA® in combination with TAXOTERE®, Carboplatin, and HERCEPTIN® (TCH). Following surgery, patients should continue to receive HERCEPTIN® to complete 1 year of treatment. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. Gianni L, Pienkowski T, Im YH, et al. Lancet Oncol. 2012;13:25-32
Chronic immunosuppression as seen in patients with HIV and in patients undergoing solid organ transplantation, may increase the risk for HPV infections. Patients with HPV associated oropharyngeal cancer typically are younger males, tend not to smoke or drink and present with poorly differentiated, non keratinizing tumors with basaloid morphology, compared to those with HPV negative tumors. Clinical characteristics of HPV positive oropharyngeal cancer patients with best outcomes include, those with fewer than 10 pack year smoking history and lower tumor stage. Several retrospective trials as well as some small prospective studies have shown that HPV positive oropharygeal cancers when treated with chemoradiation have significantly higher response rates, progression free survival, overall survival and better local and regional disease control. In the TAX 324 randomized phase III trial, patients received induction treatment with 3 cycles of TAXOTERE®, Cisplatin and 5-Fluorouracil (5-FU) or Cisplatin and 5-FU followed by chemoradiation with concurrent PARAPLATIN® (Carboplatin). Even though the 3 drug induction treatment group had superior outcomes compared to those who received 2 drug induction regimen in the intent to treat population, on retrospective analysis, patients with HPV positive oropharyngeal cancer had a significantly longer 5 year progression free survival (78% vs 28%) and overall survival, with an 80% reduction in mortality (HR=0.20, P<0.0001), compared to HPV negative patients, regardless of induction treatment. Other studies have shown that HPV positive patients who undergo surgery alone for oropharyngeal cancer do not appear to reap these favorable benefits, suggesting that the improved prognosis in the HPV positive patients with oropharyngeal cancer is related to chemotherapy and radiation. It also appears that HPV positive patients with oropharyngeal cancer have a better prognosis with treatment when their tumors are P53 wild type and express P16. With regards to EGFR and P16, there appears to be an inverse correlation between P16 and EGFR expression and patients with tumors expressing P16 and not EGFR have a significantly higher 5 year disease free and overall survival compared to those whose tumors overexpress EGFR but not P16. This information may have significant therapeutic implications and studies are underway trying to address this group of patients with targeted and less intense treatments. It should be noted that HPV positive status has a favorable prognostic value only for oropharyngeal primary cancers and not for other cancers of the head and neck.
The AZURE investigators conducted a study to determine whether the addition of RECLAST® (Zoledronic acid) to standard adjuvant therapy would improve disease outcomes in patients with early-stage breast cancer. They noted that in the subset analysis, the addition of RECLAST® significantly improved disease free survival and overall survival in postmenopausal patients, independent of estrogen receptor status, tumor stage, and lymph node involvement (N Engl J Med 2011;365:1396-1405). With this background, the authors belonging to the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), conducted a meta-analysis and reviewed data from 15 years of bisphosphonate trials, which included 36 trials of adjuvant bisphosphonates in breast cancer and involved over 17,000 pre and postmenopausal women. RECLAST® (Zoledronic acid) and Clodronate were the most common bisphosphonates used in these trials. The primary outcomes analyzed were time to distant recurrence, local recurrence, new second primary breast cancer (ipsilateral or contralateral), time to first distant recurrence (ignoring any previous locoregional or contralateral recurrences), and breast cancer mortality. Planned subset analyses included site of recurrence, site of first distant metastasis (bone vs other), menopausal status (pre, peri and post) type of bisphosphonate (aminobisphosphonates such as RECLAST® or Clodronate) and drug schedule of bisphosphonate therapy (for bone protection vs advanced cancer). Adjuvant bisphosphonates resulted in a 34% reduction in the risk of bone recurrence (P = 0.00001) and a 17% reduction in the risk of breast cancer death (P =0.004). This benefit was seen regardless of estrogen receptor status, nodal status or whether chemotherapy was used or not. Bisphosphonates had no significant impact on non-breast cancer related deaths, contralateral breast cancer or loco-regional recurrence. In this meta-analysis, all these benefits were only seen in postmenopausal women and premenopausal women had no benefit on any disease outcomes with bisphosphonates. The authors emphasized that low estrogen environment as is seen in postmenopausal women, or women rendered menopausal by suppression of ovarian function is a prerequisite for adjuvant bisphosphonate activity. Based on this large meta-analysis, the authors recommended the use of RECLAST® once every six months or oral Clodronate, where available. Because of paucity of data, they do not recommend the use of weekly dose of oral bisphosphonates, often used to prevent osteoporosis, to achieve these benefits. Coleman R, Gnant M, Paterson A, et al. San Antonio Breast Cancer Symposium 2013; San Antonio, TX. Abstract S4-07.
The SELECT trial, which began in 2001, was stopped early in 2008, as Selenium and Vitamin E, taken alone or together for an average of five and a half years did not decrease the incidence of prostate cancer. In 2011, an update on the SELECT trial data suggested that men who were randomized to the vitamin E alone had a 17 percent increased risk of prostate cancer compared to those men taking placebo. The authors in this case–cohort study continued follow up of the SELECT trial participants and with the Selenium levels data from toenail clippings, compared the effect of Selenium and Vitamin E, taken either alone or together, on the risk of prostate cancer, among 1739 men who were diagnosed with prostate cancer, of whom 489 participants developed high-grade prostate cancer. The control group for comparison was a random sample of 3117 men without prostate cancer and they were matched to the cases by race and age. It was noted that an individual’s baseline Selenium level, in the absence of supplementation, was not associated with prostate cancer risk. However, in men who had high baseline Selenium levels, Selenium supplements almost doubled (91%) the risk of high grade prostate cancer (P=0.007). Conversely, Vitamin E supplements had no effect among men with high baseline Selenium levels but doubled the risk of high grade prostate cancer among men with low baseline Selenium levels. Frankel et al. in an accompanying editorial point out that the dose of Vitamin E in the SELECT trial was significantly higher (400 IU/day) than the dose that was selected in the Alpha-Tocopherol Beta Carotene (ATBC) Cancer Prevention trial (50 IU/day), a study that was designed to test Vitamin E and beta carotene for lung cancer prevention in smokers. In the ATBC trial, a decrease in the incidence of prostate cancer incidence was observed, although this was a secondary finding and this study was not designed to determine prostate cancer risk. They comment that high doses of Vitamin E (Alpha-Tocopherol), suppresses the more potentially beneficial serum Gamma-Tocopherol which is the prevalent dietary form of Vitamin E in the United States. Selenium deficiency in the U.S. is not common and any benefit with Selenium supplements can only be seen in those who are Selenium deficient and high doses may be detrimental. The authors concluded that in the SELECT trial, the combination of both Vitamin E and Selenium did not reduce the risk of prostate cancer or any other cancer or heart disease and was in fact harmful for a significant number of individuals. Therefore, men 55 years of age or more should avoid Vitamin E or Selenium supplements at doses that exceed the recommended dietary intake. Kristal AR, Darke AK, Morris JS, et al. J Natl Cancer Inst; First published online 22 February 2014, doi: 10.1093/jnci/djt456