Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
121
treat serious diseases and to help ensure patients have access to them through FDA
approval as soon as possible.
Additional ALK inhibitors currently undergoing clinical trials include AP26113
(Ariad), NMS-E628 (Nerviano, licensed by Ignyta and renamed RXDX-101),
PF-0643922 (Pfizer), TSR-011 (Tesaro), CEP-37440 (Teva), and X-396 (Xcovery).
Although these agents are still at the early development stage, the preliminary evidence
indicates activity in patients with acquired resistance to crizotinib, increased
ALK selectivity and greater potency, and the potential for intracranial disease
responses.
In addition to EGFR, ALK, and KRAS, many studies revealed that NSCLC can
also be stratified by recurrent “driver” mutations in multiple other oncogenes, including
AKT1, BRAF, HER2, MEK1, NRAS, PIK3CA, RET, and ROS1. These “driver”
mutations lead to constitutional activation of mutant signaling proteins that induce
and sustain tumorigenesis. These mutations are rarely found concurrently in the same
tumor. Mutations can be found in all NSCLC histologies, including adenocarcinoma,
squamous cell carcinoma (SCC), and large cell carcinoma. The highest incidence of
EGFR, HER2, ALK, RET, and ROS1 mutations has been found in lifelong nonsmokers
with adenocarcinoma. As discussed above, targeted small molecule inhibitors
are currently available or being developed for specific subsets of patients with a
specific molecular profile. Therefore, molecular profiling by NGS of these multiple
genes with concurrent FISH for ALK and ROS1 will stratify treatment for directing
patients toward beneficial therapies and away from unfavorable ones.
GENETIC TESTING FOR INHERITED CANCER SUSCEPTIBILITY
Genetic susceptibility (also known as genetic predisposition) is defined as the
increased likelihood or chance of developing a particular disease due to the presence
of one or more gene mutations and/or a family history that indicates an increased risk
of the disease. Cancer etiology is a result of interactions of multiple factors, including
genetic, medical, environmental, and lifestyle factors. Although only a small portion
of cancers are inherited, numerous cancer susceptibility syndromes and their
causative genes have been identified (Lindor et al. 2008). Mutations and variants
of the cancer susceptibility genes are associated with an increased risk of cancers,
including breast cancer, ovarian cancer, colorectal cancer (CRC), thyroid cancer,
hereditary diffuse gastric cancer (HDGC), and many other types of cancers (Garber
and Offit 2005; Lindor et al. 2008) (see Table 5.3 for selected examples). Genetic
testing provides the benefit of early detection and all aspects of cancer management,
including prevention, screening, and treatment. An example for clinical intervention
is prophylactic salpingo-oophorectomy for individuals carrying mutations in the
BRCA1 or BRCA2 gene (Daly et al. 2010; Domchek et al. 2010; Kauff et al. 2002).
The importance of inherited cancer risk has long been recognized, and the American
Society of Clinical Oncology (ASCO) released its first statement on genetic testing in
1996 to give specific recommendations for cancer genetic testing (1996). This policy
statement was updated in 2003, 2008, and 2010 (Robson et al. 2010).
Based on the penetrance, which refers to the proportion of individuals carrying
a mutation or a variant who will develop cancer, there are three types of mutations