Personalised cancer medicine
TL;DR: The efficacy of various targeted therapies in such disparate tumours suggests that the authors are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or “signature,” rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life.
Abstract: The evolving field of personalised medicine is playing an increasingly important role in cancer prevention, diagnosis, prognosis and therapeutics. Its importance in clinical management is demonstrated by the recent introduction into routine clinical practice of various individualised, molecularly targeted therapies with increased efficacy and/or reduced toxicity. The identification of cancer predisposition genes, such as the BRCA genes in breast cancer, permits screening programmes to identify patients “at-risk” of developing cancer and helps them make decisions on individual risk-modification behaviours. Personalised medicine also plays an increasingly important role in cancer treatment. It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2-positive breast cancer and wild-type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non-small-cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer. The efficacy of various targeted therapies in such disparate tumours suggests that we are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or “signature,” rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life. This mini review focuses on the role of personalised medicine in cancer prevention and treatment as well as its future direction in oncology.
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TL;DR: This work tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases, including Huntington's disease and multiple spinocerebellar ataxias.
Abstract: Objective
The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.
Methods
We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.
Results
In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.
Interpretation
We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016
164 citations
TL;DR: When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers.
Abstract: TROP-2 is a glycoprotein first described as a surface marker of trophoblast cells, but subsequently shown to be increased in many solid cancers, with lower expression in certain normal tissues. It regulates cancer growth, invasion and spread by several signaling pathways, and has a role in stem cell biology and other diseases. This review summarizes TROP-2's properties, especially in cancer, and particularly its role as a target for antibody-drug conjugates (ADC) or immunotherapy. When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers.
161 citations
Cites background from "Personalised cancer medicine"
...Precision medicine now represents the focus of most anticancer therapies in development, based on the identification of targetable gene mutations and marker proteins that lead to more selective methods of prevention, diagnosis and therapy [1]....
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TL;DR: Tumour budding in CRC is strongly predictive of lymph node metastases, recurrence and cancer-related death at 5 years, and its incorporation into the CRC staging algorithm will contribute to more effective risk stratification.
Abstract: Tumour budding is a histological finding in epithelial cancers indicating an unfavourable phenotype. Previous studies have demonstrated that it is a negative prognostic indicator in colorectal cancer (CRC), and has been proposed as an additional factor to incorporate into staging protocols. A systematic review of papers until March 2016 published on Embase, Medline, PubMed, PubMed Central and Cochrane databases pertaining to tumour budding in CRC was performed. Study end points were the presence of lymph node metastases, recurrence (local and distal) and 5-year cancer-related death. A total of 7821 patients from 34 papers were included, with a mean rate of tumour budding of 36.8±16.5%. Pooled analysis suggested that specimens exhibiting tumour budding were significantly associated with lymph node positivity (OR 4.94, 95% CI 3.96–6.17, P<0.00001), more likely to develop disease recurrence over the time period (OR 5.50, 95% CI 3.64–8.29, P<0.00001) and more likely to lead to cancer-related death at 5 years (OR 4.51, 95% CI 2.55–7.99, P<0.00001). Tumour budding in CRC is strongly predictive of lymph node metastases, recurrence and cancer-related death at 5 years, and its incorporation into the CRC staging algorithm will contribute to more effective risk stratification.
159 citations
Cites background from "Personalised cancer medicine"
...Personalised patient care is an emerging concept in the future of cancer treatment (Piccart, 2013; Wazir and Mokbel, 2014; Jackson and Chester, 2015), and incorporation of tumour budding into the staging of CRC could assist in tailoring the management of currently contentious subgroups (Koelzer et…...
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...Personalised patient care is an emerging concept in the future of cancer treatment (Piccart, 2013; Wazir and Mokbel, 2014; Jackson and Chester, 2015), and incorporation of tumour budding into the staging of CRC could assist in tailoring the management of currently contentious subgroups (Koelzer et al, 2016)....
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TL;DR: An overview of the optimal 'design-to-perform' MNPs used in cancer therapeutics, specifically focusing on magnetic hyperthermia, magnetic drug targeting, and targeting delivery is provided.
137 citations
TL;DR: This commentary discusses hypothetical explanations and takes a step beyond BMI or simple weights alone to present other useful and more specific body composition metrics, such as muscle tissue mass, visceral fat mass, and subcutaneous fat mass.
Abstract: Body mass index (BMI) and simple counts of weight are easy and available tools in the clinic and in research. Recent studies have shown that cancer patients with a low normal BMI (or those with weight loss) have worse outcomes than obese patients. These results suggest that obesity has a protective effect and has been termed the "obesity paradox." In this commentary, we discuss hypothetical explanations and take a step beyond BMI or simple weights alone to present other useful and more specific body composition metrics, such as muscle tissue mass, visceral fat mass, and subcutaneous fat mass. Body composition is highly variable between individuals with significant differences seen between various races and ages. Therefore, it is critical to consider that patients with the exact same BMI can have significantly different body compositions and different outcomes. We encourage further studies to examine body composition beyond BMI and to use other body composition metrics to develop individualized treatments and intervention strategies. Cancer Epidemiol Biomarkers Prev; 26(1); 13-16. ©2017 AACR SEE ALL THE ARTICLES IN THIS CEBP FOCUS SECTION, "THE OBESITY PARADOX IN CANCER EVIDENCE AND NEW DIRECTIONS".
105 citations
Cites background from "Personalised cancer medicine"
...The evolving field of personalized medicine in oncology is playing an increasing role in cancer prevention, diagnosis, prognosis, and therapeutics (38)....
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References
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TL;DR: Gefit inib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia and the presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.
Abstract: METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)
7,246 citations
"Personalised cancer medicine" refers background in this paper
...In those patients with an EGFR mutation treated with gefitinib, progression-free survival was longer, whereas in EGFR mutation-negative patients progression-free survival was longer when treated with standard chemotherapy.(37) Improved progression-free survival in EGFR mutation patients treated with gefitinib was confirmed in another phase III study....
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Memorial Sloan Kettering Cancer Center1, University of Kiel2, Institut Gustave Roussy3, Netherlands Cancer Institute4, The Royal Marsden NHS Foundation Trust5, University of Zurich6, University of Tübingen7, University of Manchester8, University of Paris9, University of Duisburg-Essen10, University of California, Los Angeles11, Vanderbilt University12, University of Pittsburgh13, University of Nantes14, Plexxikon15, Hoffmann-La Roche16, Genentech17, Harvard University18, Peter MacCallum Cancer Centre19
TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
6,773 citations
"Personalised cancer medicine" refers background in this paper
...Treatment with vemurafenib, a potent and selective Raf inhibitor, reduced the relative risk of mortality by 63% and the risk of death or disease progression by 74% in patients with unresectable, previously untreated stage IIIC/IV BRAF V600E mutation-positive malignant melanoma, compared to standard treatment.(31) Vemurafenib has consequently been approved in America and Europe as individualised therapy for treating patients with BRAF V600E mutation-positive unresectable or metastatic malignant melanoma....
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...Stage IV malignant melanoma is a disease with very poor prognosis–median survival at diagnosis is only 18 months.(31) M in i R ev ie w 264 Personalised cancer medicine...
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TL;DR: Elotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy, and five percent of patients discontinued erlot inib because of toxic effects.
Abstract: Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects. conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after firstline or second-line chemotherapy.
5,157 citations
TL;DR: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Abstract: Background BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic res...
5,037 citations
"Personalised cancer medicine" refers background in this paper
...In chronic myeloid leukaemia (CML), a reciprocal translocation between the long arms of chromosome 9 and 22, termed the Philadelphia chromosome, results in expression of a BCR-ABL fusion oncoprotein with constitutive tyrosine kinase (TK) activity.(36) This promotes tumourigenesis but also provides an “Achilles’ heel,” ripe for exploitation by tumourselective, molecularly targeted therapy....
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TL;DR: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations as discussed by the authors.
Abstract: Summary Background Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m 2 on day 1 plus docetaxel (75 mg/m 2 on day 1) or gemcitabine (1250 mg/m 2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m 2 or AUC 5 with gemcitabine 1000 mg/m 2 ) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Findings Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Tematica de Investigacion Cooperativa en Cancer.
4,791 citations