Globally, cancer is a leading cause of death. Conventional chemotherapy has been the mainstay of cancer therapy. Chemotherapy inhibits rapidly dividing cells like cancer cells, but in this process, normal cells of the body like epithelial cells of the gut, bone marrow, skin, and hair follicles are also affected which are responsible for the adverse reactions of chemotherapy. Targeted therapies are drugs that block the growth and spread of cancer by interfering with specific molecules like genes or proteins (molecular targets) that are involved in the growth, progression, and spread of cancer. By focusing on specific molecular changes which are unique to particular cancer, targeted therapies are advantageous in terms of being more selective, enhanced response, fewer effects on normal cells, and consequently fewer adverse reactions.
Advances in medicine have enabled the analysis of various molecular changes which occur in cancer cells and invent novel drugs which have dramatically changed the treatment landscape of cancer. This revolution in cancer therapy is exemplified by imatinib in the treatment of chronic myeloid leukemia (CML). CML which was once a fatal disease with only a few months of survival once diagnosed, has now turned into a chronic disease compatible with normal life with the advent of targeted drugs like imatinib and dasatinib. Similarly, patients with lung cancer had a median survival of about 1 year, but after the arrival of targeted drugs like EGFR and ALK inhibitors the median survival has now increased to more than 5 years.
A 56-year-old female presented with a history of gradually progressing dyspnea over 3 months. CT chest revealed bilateral extensive lung infiltrates. Image-guided biopsy was suggestive of adenocarcinoma of lung. Molecular testing by FISH revealed EML4-ALK fusion. The patient was treated with crizotinib and a CT scan after 3 months showed an excellent response to therapy (figure 1).
Figure 1: Baseline CT scan of a patient with ca lung (left) and response CT scan after 3 months of therapy with crizotinib, an ALK inhibitor (right).
A 60-year-old gentleman presented with dry cough for 2 months. CT chest revealed right lung mass with collapse and consolidation and right pleural effusion. CT-guided biopsy revealed adenocarcinoma of lung. Molecular testing for EGFR by RT-PCR revealed exon 19 deletion. The patient was treated with osimertinib 80mg once daily. Response scan after 3 months showed dramatic response to treatment with almost complete resolution of lung mass and effusion (figure 2).
Figure 2: Baseline CT scan of a patient with metastatic ca lung (left) and response CT scan after 3 months of therapy with Osimertinib (an EGFR inhibitor) (right).
Numerous genetic changes like point mutations, gene insertions or deletions, gene amplification, or protein expression occur in cancer. They may lead to activation of proto-oncogene or inactivation of tumor suppressor gene and may lead to tumorigenesis.
Point mutations result from single nucleotide substitutions. Examples of point mutations leading to cancer are EGFR L858R mutation in lung cancer. The anti-EGFR drugs like geftinib, afatinib, osimertinib are highly effective against this type of lung cancer. In BRAF V600E mutant melanoma, BRAF directed therapy with dabrafenib and trametinib are associated with impressive response rates. Similarly, MET exon 14 mutation in lung cancer is inhibited by capmatinib and tepotinib. Point mutations are commonly detected by reverse transcriptase PCR (RT- PCR) or sanger sequencing or more commonly by next-generation sequencing (NGS).
Nucleotides can inserted or deleted, in the coding portions (exons) of the genome in cancer cells and can be targetted with drugs. For example, lung cancer with EGFR exon 20 insertion, can be treated with poziotinib or amivantamab which are highly specific for this type of EGFR alteration. Point mutations, insertions, and deletions are detected by reverse transcriptase PCR (RT- PCR) or sanger sequencing or more commonly by next-generation sequencing (NGS).
Certain cancers acquire more than one copy of a particular gene eg. HER2 amplification in breast cancer which can be targeted with anti-HER2 drugs like trastuzumab, pertuzumab, lapatinib, etc. Sometimes different parts of the genome are fused together to form gene fusions eg. EML4- ALK fusion in lung cancer, BCR- ABL fusion in Chronic myeloid leukemia. Fluorescent in situ hybridization (FISH) and NGS are the methods commonly used to detect gene amplification and fusion.
Overexpression of growth factors or growth factor receptors can lead to the transformation of a normal cell into a cancer cell. Eg, HER2 overexpressing breast cancer can be inhibited by trastuzumab, Androgen receptor expressing breast cancer can be inhibited by anti-androgens like bicalutamide, enzalutamide. Protein overexpression can be detected by immunohistochemistry (IHC) of pathological tumor specimens.
Although targeted therapy has revolutionized the management of cancer, it has its limitations. A targetable genomic alteration may not be always found in every patient. Targeted drugs are not available for several other genomic abnormalities (eg. p53 mutation) although a large number of newer drugs are in the pipeline. Resistance to targeted therapy is also possible after long-term treatment with these agents.
Targeted therapy has dramatically changed the treatment paradigm of oncology and has become the mainstream in cancer treatment. With an in-depth understanding of tumor pathology and the evolution of new drug research and development technology, newer and newer anti-cancer drugs that target novel genes or the mechanism of action will be available in the future.
Dr. Suresh Kumar. B Associate Consultant – Medical Oncology Kauvery Hospital Chennai
