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Lung Cancer Figure 3: ECOG 1505 Trial Overview


Eligible: n=1,500


Resected IB–IIIA (IB ≥4cm)


≥Lobectomy No prior chemotherapy No planned XRT


Stratified: • Stage


• Histology • Gender


• Chemotherapy regimen:


(Investigator choice) Cisplatin/vinorelbine Cisplatin/doxetaxel Cisplatin/gemcitabine Cisplatin/pemetrexed


Primary end-point: overall survival.


ECOG = Eastern Cooperative Oncology Group; XRT = radiotherapy. Figure 4: MAGRIT Trial Overview


Eligible: n=2,270


Resected IB–IIIA


MAGE A3 Expression (35–50% of NSCLC)


Stratified:


• Adjuvant chemotherapy


Randomised


Placebo injection x 13 over 27 months


Primary end-point: disease-free survival.


MAGRIT = MAGE-A3 as Adjuvant, Non-Small Cell Lung Cancer Immunotherapy; NSCLC = non-small-cell lung cancer.


Figure 5: RADIANT Trial Overview Stratified:


Eligible: n=945


Resected I–IIIA


≥ Lobectomy Required IHC/ FISH for EGFR Chemotherapy optional


• Histology (squamous versus other) • Gender • Age • EGFR status • Smoking status • Adjuvant chemotherapy


Only randomised if IHC or copy number positive


Erlotinib 150mg PO every day x 2 years


Randomised 2:1


Placebo tablet PO every day x 2 years


Vaccine injection x 13 over 27 months


Randomised


Chemotherapy x 4 cycles plus


bevacizumab x 1 year


Chemotherapy x 4 cycles


in patients with completely resected, chemotherapy-naive NSCLC.33 BRCA1 messenger RNA (mRNA) expression has been linked to resistance to DNA-damaging reagents, such as cisplatin and etoposide, while functioning as a sensitiser to antimicrotubule drugs, such as taxanes and vinca alkaloids. BRCA1 mRNA expression is being evaluated as a method to customise adjuvant chemotherapy in the Spanish customised adjuvant trial (SCAT) trial (see below).34


Thymidylate Synthase


In a randomised phase III trial comparing pemetrexed/cisplatin with gemcitabine/cisplatin, survival was superior in patients with non-squamous histology receiving the pemetrexed-based regimen.35,36 Using the histological classification for a therapeutic decision led the US Food and Drug Administration (FDA) to limit pemetrexed therapy to only patients with nonsquamous NSCLC. The treatment outcome difference using pemetrexed in different histologies is likely to be due to an underlying difference in thymidylate synthase (TS). TS is an enzyme that is important for DNA biosynthesis and a target of fluoropyrimidine- and pemetrexed-based therapies. Low TS expression levels have been associated with a better response to pemetrexed.37,38


Although TS mRNA expression is on average lower in groups of patients with non-squamous histologies compared with squamous histologies, there is significant overlap of expression ranges in individual patient tumours. Further analysis of the relationship between chemotherapy and TS is being studied prospectively in the international ITACA phase III trial.


Class III β-tubulin


Tubulins are a family of globular proteins that make up microtubules in cells. They are important for many aspects of the cell, including structure, movement, mitosis and vesicular transport. The expression of class III β-tubulin (βTubIII) was studied in the JBR.10 study. IHC was performed for βTubIII on 265 out of 482 resected tumour specimens, and a high level of expression was correlated with a better relapse- free survival and overall survival in patients who received the adjuvant chemotherapy.39


resistance to antimicrotubule reagents.40


A high expression of βTubIII correlates with Further prospective studies


Primary end-point: disease-free survival. EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridisation; IHC = immunohistochemistry; PO = orally; RADIANT = Randomized Double-blind Trial in Adjuvant NSCLC with Tarceva.


benefit from adjuvant chemotherapy, but the p53 mutation was not a predictive marker for adjuvant chemotherapy. The utility of this marker for adjuvant therapy is therefore indeterminate at this time.


Insulin-like Growth Factor Receptor 1


The prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected NSCLC was recently undertaken.32 IGF1R expression was evaluated by IHC in tissue microarray sections. Although a positive IGF1R expression was significantly associated with squamous cell histology, there was no difference in survival between the positive and negative groups. Therefore, IGF1R expression does not appear to be a prognostic factor in resected NSCLC patients. If IGF1R targeted agents prove to have some efficacy in advanced stage NSCLC, they are likely to be further investigated in early-stage disease.


Breast Cancer 1


Breast cancer 1 (BRCA1) is a member of the DNA mismatch repair pathway. Overexpression of BRCA1 correlates with poor overall survival


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are needed to validate the utility of βTubIII. Although to date most of the aforementioned biomarkers have not been integrated into practice, there are numerous ongoing clinical trials to address the utility of these genetic biomarkers for clinical treatment decisions.


Genomic and Proteomic Signatures


The genetic signature was validated in four separate microarray data sets. The same signature predicted survival of those patients with early-stage, completely resected NSCLC who received adjuvant cisplatin/vinorelbine. This demonstrates the potential to select patients with early-stage (IB–II) NSCLC that are most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine but it needs further validation. Multiple other gene signatures are under investigation. In addition to genomic signatures, studies using proteomics have been developed to classify which patients might respond to receptor TKIs.42–45


Although this is used in advanced NSCLC, the same proteomic signatures are now being applied to EUROPEAN ONCOLOGY & HAEMATOLOGY


Several gene expression signatures containing non-overlapping genes may provide predictive information on clinical outcome. Recently, a 15-gene signature was identified in patients from the JBR.10 trial observation arm that separated the group into high-risk and low-risk subgroups with significantly different survival (HR 15.02, 95% CI 5.12 to 44.04; p<0.001; stage I HR 13.31; p<0.001; stage II HR 13.47; p<0.001).41


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