predict pathological complete response to neoadjuvant taxane-anthracycline-based chemotherapy. To this end, many new PARP inhibitor compounds are under investigation for both breast and ovarian cancers. O’Shaughnessy and colleagues have presented, in abstract form, early results of one such compound in patients with triple- negative breast cancer, measurable disease, and a history of no more than two prior cytotoxic regimens. These patients were randomized to receive gemcitabine and carboplatin, with (n = 42) or without (n = 44) the PARP1 inhibitor, BSI-201. A clinical benefit rate (defined as having achieved a complete or partial response or having achieved stable disease for at least six months) was achieved in 52% of patients receiving chemotherapy with BSI-201 and 12% of patients receiving chemotherapy alone (p=0.0012). BSI-201 was well tolerated. Updated results from this Phase II trial have shown that BSI-201, now called iniparib, given with gemcitabine plus carboplatin led to statistically significant improvements in the rate of clinical benefit (from 34% to 56%) and the rate of overall response (from 32% to 52%). Addition of iniparib to chemotherapy in patients with metastatic triple-negative breast cancer also led to improvements in median progression-free survival (from 3.6 months
12
www.lifesciencesmagazines.com
to 5.9 months) and median overall survival (from 7.7 months to 12.3 months).
INDIVIDUAL CHEMOTHERAPY IN LUNG CANCER Lung cancer, the leading cause of cancer death in both men and women, has also been studied at length and provides two more examples of individualized chemotherapy to be reviewed here. In the first example, the oncogene Her1, also known as c-erb-B1, is another member of the epidermal growth factor family of receptors (EGFR). Like Her2, Her1 encodes for a transmembrane glycoprotein that has intracellular tyrosine kinase activity. Her1 expression can be found in both normal tissue (skin, hair follicle) and cancerous tissue (head and neck, colorectal, lung). Kris and colleagues conducted a single institution, prospective evaluation of various recurrent mutations in patients diagnosed with lung adenocarcinoma with sufficient
“Pharmacologic agents play a major role in the treatment of neoplastic disorders”
tissue for sampling. Of the 541 samples evaluated, 119 (22%) were positive for EGFR mutation, leading to the conclusion that mutational data can be used to select EGFR tyrosine kinase inhibitors (such as erlotinib or gefitinib) for individuals with EGFR mutations. A second example of personalised
chemotherapy in lung cancer is provided by the uncommon EML4-ALK mutation. This mutation, found in up to 8% of all non-small cell lung cancers (NSCLC), is more prevalent in patients who have a negative or light smoking history, an adenocarcinoma sub-type. This gene encodes for a cytoplasmic chimeric protein with constitutive kinase activity. Kwak and colleagues have conducted a multi- institutional, phase I, two-part, expanded cohort trial of 82 patients with ALK-positive, measurable NSCLC. ALK rearrangement was confirmed by fluorescence in situ hybridization (FISH); previous chemotherapy treatment was allowed. Patients were given crizotinib (PF-02341066), a small molecule ATP-competitive selective inhibitor of ALK tyrosine kinase, at a maximum tolerated dose of 250 mg orally twice daily. Patients were treated until disease progression or intolerance of side effects. Overall response rate was 57% (1 complete response + 46 partial responses from 82 patients); stable
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40