Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.
However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations. Continue reading…
The gist: Afatinib (Gilotrif) works better than chemotherapy for people with non-small cell lung cancer (NSCLC) whose tumors have a specific mutation in the EGFR gene. This mutation is known as exon 19 deletion. In a recent clinical trial, some patients with exon 19 deletion were treated with Gilotrif and some with chemotherapy. The patients who received Gilotrif lived significantly longer than the patients who received chemotherapy. All patients had stage IIIB or IV lung adenocarcinoma.
“Patients with lung adenocarcinoma who harbored exon 19 deletion EGFR mutations experienced significantly longer OS when treated with first-line afatinib instead of chemotherapy, according to analyses of results from two phase 3 trials.
“However, researchers did not observe the survival benefit among patients with other types of EGFR mutations.
“ ‘These data provide important evidence about the use of afatinib in patients whose tumors have the del19 mutation and tell us that the standard treatments and approaches should no longer be assumed equivalent for every EGFR mutation,’ Lecia V. Sequist, MD, MPH, medical oncologist at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School, said in a press release.”
“The American Society of Clinical Oncology (ASCO) has endorsed a clinical practice guideline from several other professional associations aimed at guiding decisions on when to offer molecular testing for epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in patients with non–small-cell lung cancer (NSCLC). Research on drugs targeting some of these mutations has exploded in recent years, and clinicians in practice may have had trouble keeping up with when exactly testing should be done in order to guide use of those new therapies.
“ ‘This guideline is incredibly important, as it increases the ability to personalize lung cancer care and improve outcomes for patients with advanced lung cancer,’ said Natasha B. Leighl, MD, co-chair of ASCO’s panel that endorsed the new guideline, in a press release. ‘It describes the current evidence and helps oncologists and pathologists understand and put molecular testing into clinical practice.’
“The guideline is a joint product of the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. It contains 37 distinct recommendations, opinions, or suggestions, focusing on when to test for EGFR and ALK mutations; it was published on October 13 online in the Journal of Clinical Oncology.
“The primary recommendation is to offer EGFR and ALK testing to all patients with lung adenocarcinoma (or mixed lung cancers with an adenocarcinoma component), regardless of characteristics such as smoking status, gender, or race. Small tumor samples of other histologies could be considered for testing, particularly if ‘clinical criteria are suggestive’—this would include younger age, and a lack of smoking history, among other factors.”
The gist: For certain types of cancer, oncologists might use molecular testing to help figure out a patient’s treatment options. Molecular testing can uncover certain genetic mutations that might make a tumor treat-able with certain kinds of drugs. Many patients with lung adenocarcinomas are already tested for EGFR mutations; a person with an EGFR mutation could be treated with an “EGFR inhibitor” drug, such as erlotinib (aka Tarceva). Now, a new guideline states that all patients with lung adenocarcinoma should be tested for both EGFR mutations and a mutation known as ALK rearrangement. Testing for these two mutations could show which patients could benefit from which targeted therapy drugs.
“ASCO today endorsed a joint clinical practice guideline from three other entities that addresses questions about the appropriate use of EGFR-mutation and ALK-rearrangement testing in patients with lung cancer.
“A key recommendation from the guideline — developed by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology — states that clinicians should offer EGFR and ALK testing to all patients with lung adenocarcinoma, as well as those with mixed lung cancer with an adenocarcinoma component.
“The testing should be offered regardless of characteristics — such as smoking status, gender and race — to help determine which patients could benefit from targeted therapy with tyrosine kinase inhibitors, according to the guideline.
“ ‘This guideline is incredibly important, as it increases the ability to personalize lung cancer care and improve outcomes for patients with advanced lung cancer,’ Natasha B. Leighl, MD, MSc, medical oncologist at Princess Margaret Hospital in Toronto and co-chair of the ASCO expert panel that reviewed and endorsed the guideline, said in a press release. ‘It describes the current evidence and helps oncologists and pathologists understand and put molecular testing into clinical practice.’
“Patients with advanced-stage disease should be offered testing at the time of diagnosis, and patients with lower-stage disease should undergo testing at the time of progression or recurrence, the guideline states.”
The gist: Oncologists can sometimes look for certain genetic mutations in a patient’s tumor to help determine the best treatment options for that patient. Researchers have recently found that a particular mutation called ROS1 fusion is present in a subgroup of patients consisting of young East Asian patients with lung adenocarcinoma. People with ROS1 mutations in their lung tumors might benefit from treatment with a drug called crizotinib. The drug has not yet been approved for widespread use by the U.S. Food and Drug Administration (FDA), but patients can enroll in clinical trials to gain access to it.
“ROS1 fusion genes were successfully detected independent of gender or smoking history in young East Asian patients with lung adenocarcinoma, a histological subgroup in non-small cell lung cancer (NSCLC), using multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) diagnostic tests.
“In NSCLC treatment algorithms, a personalized therapy approach is now being taken based on the genetic characteristics of the cancer. Patients with specific oncogenic molecular aberrations, for example EGFR mutations and ALK gene fusions, respond well to drugs that target these molecular abnormalities. ROS1 is another potential oncogenic molecular driver and this target is sensitive to crizotinib, a drug approved for the treatment of ALK gene fusion NSCLC patients.
“Researchers from the National Taiwan University Hospital examined 160 surgical specimens from early-stage lung adenocarcinoma and 332 specimens of fluid around the lungs (malignant pleural effusions) from late-stage lung adenocarcinoma patients. They initially examined these specimens for EGFR and KRAS mutations as well as ALK gene. Specimens that were negative for these three oncogenic drivers were then examined for ROS1 fusions using RT-PCR and IHC. Fluorescence in situ hybridization (FISH) was used if there was a discrepancy between RT-PCR and IHC.”
Nadal E, Chen G, Gallegos M, Lin L, et al. Clinical Cancer Research. Oct 15, 2013.
The microRNA-34b/c (miR-34b/c) has been considered a tumor suppressor in different tumor types and it is a known transcriptional target of the tumor suppressor gene TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in early stage lung adenocarcinoma (AC) patients and to determine the functional role of miR-34b/c re-expression in lung AC cell lines.
Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in early stage lung AC patients with surgically resected tumors. Re-expression of miR-34b/c leads to a less aggressive phenotype in lung AC cell lines.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, et al. J Clin Oncol. Jun 25, 2013.
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation–positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).
In this phase III study, it was found that afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Xu C, Xie D, Yu SC, Yang XJ, et al. Cancer Res. Mar 28, 2013.
“Cancer stem-like cells (CSLCs) are crucial in tumor initiation and progression, however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma (LAC) showed that high expression of insulin-like growth factor 1 receptor (IGF-1R) in LAC cells was positively correlated with the expressions of cancer stem cell markers, CD133 and ALDH1A1…”
Watanabe M, Yokose T ... NakayAama H, Fujino S, Lung Cancer, Feb 20, 2013
We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump.