Predictive Marker For Benefit Research Articles

Atezolizumab plus chemotherapy with or without bevacizumab in advanced biliary tract cancer: Results from a randomized proof-of-concept phase II trial (IMbrave151).

435 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that augments response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blinded, global proof-of-concept Phase II study evaluating atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for advanced biliary tract cancer (aBTC). Here we report updated clinical data and molecular correlates of response and resistance. Methods: Patients (pts) with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo (plb) + CisGem (Cis 25 mg/m2 and Gem 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or plb until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The final OS analysis was done when ≈90 deaths occurred or when all pts had ≥2 years of follow-up. Transcriptome analysis (n=98) and mutation profiling (n=103) were done on baseline tumor samples. This was a signal-seeking trial to estimate the treatment effect in each arm with no formal hypothesis testing. Results: In total, 162 pts were randomized to either atezo + bev + CisGem (atezo/bev; n=79) or atezo + plb + CisGem (atezo/plb; n=83). The updated PFS HR was 0.67 (95% CI: 0.46, 0.95) in favor of atezo/bev. Updated median PFS was 8.35 mo for atezo/bev and 7.9 mo for atezo/plb, with 6-mo rates of 78% and 63%, respectively. The updated OS HR was 0.97 (95% CI: 0.64, 1.47), with a median of 14.9 mo for atezo/bev and 14.6 mo for atezo/plb. Confirmed ORR was 26.6% for atezo/bev and 26.5% for atezo/plb, with median DORs of 10.28 (95% CI: 6.7, 16.7) and 6.18 mo (95% CI: 4.3, 6.7), respectively. The incidence of Grade 3/4 adverse events was 73% with atezo/bev and 74% with atezo/plb. High VEGFA gene expression was associated with an improved PFS (HR, 0.43; 95% CI: 0.22, 0.83) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Hepatocytes high gene signature also was associated with an improved PFS (HR, 0.47; 95% CI: 0.24, 0.92) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Pts with PI3k/AKT pathway mutations appeared to have worse OS than pts without mutations (HR, 3.7; 95% CI: 1.5, 9.1) with atezo/bev. Conclusions: Final analysis of the IMbrave151 study indicates a modest PFS benefit in intent-to-treat pts combining atezo with bev and chemotherapy. The trial is limited by small numbers and a non-comparative design. Exploratory analysis of correlative biomarkers suggests that high VEGF-A gene expression and hepatocytes high gene signature may be predictive markers of benefit with atezo/bev, warranting further investigation. Clinical trial information: NCT04677504 .

KIR2DS1–HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials

The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy. For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8). In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2·6 [95% CI 1·4-4·7], p=0·0015; progression-free survival, 2·7 [1·5-5·1], p=0·0013; overall survival, 2·8 [1·5-5·4], p=0·0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0·9 [0·5-1·7], p=0·85; progression-free survival, 1·1 [0·6-2·0], p=0·81; overall survival, 1·2 [0·6-2·4], p=0·53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0·018 for event-free survival and p=0·034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1·9 [0·8-4·6], p=0·16; progression-free survival, 1·4 [0·6-3·4], p=0·48; overall survival, 1·6 [0·6-4·3], p=0·33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0·024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2·1 [0·9-4·9], p=0·094; overall survival, 2·6 [0·5-12·7], p=0·21). Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed. F Hoffman La Roche.

Abstract LB203: FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer

Abstract To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.

A PERSONALIZED APPROACH TO ADJUVANT CHEMOTHERAPY FOR NON-SMALL CELL LUNG CANCER AFTER RADICAL SURGICAL TREATMENT BASED ON MOLECULAR MARKERS OF CHEMOSENSITIVITY

Despite advances in the treatment of non-small cell lung cancer (NSC LC), prognosis of advanced lung cancer is extremely poor. The search for additional treatment options to prevent local recurrence and distant metastases is of great importance. Monoresistance genes, such as ABCC5, BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, and TYMS play a significant role in tumor sensitivity to chemotherapy for NSC LC. The expression levels of these genes in tumor tissue should be assessed for personalization of adjuvant chemotherapy in patients with NSC LC.Case description. We present a clinical case of a 65-year-old patient diagnosed with non-small cell lung cancer who underwent extended combined surgery followed by 4 courses of personalized adjuvant chemotherapy. The expression levels of monoresistance genes (ABCC5, RRM1, ERCC1, TOP1, TOP2a, TUBB3, BRCA 1 and TYMS) determined by reverse-transcriptase quantitative real-time PCR (RTqPCR) were used as predictive markers of response to adjuvant chemotherapy regimen.Conclusion. Our case report demonstrated the feasibility of performing organ-preserving surgery followed by personalized adjuvant chemotherapy based on the expression levels of monoresistance genes as predictive markers of benefit from adjuvant chemotherapy.

The Importance of Distinguishing Sporadic Cancers from Those Related to Cancer Predisposing Germline Mutations.

Choosing the optimal therapy for a patient's cancer has long been based on whether the cancer demonstrates a predictive marker of efficacy. The U.S. Food and Drug Administration (FDA) has now approved use of a targeted therapy based solely on tumor molecular markers (pembrolizumab for tumors with deficient mismatch repair [MMR] and high microsatellite instability [MSI]) and approved another therapy based solely on a germline mutation as the predictive marker of benefit (olaparib for BRCA carriers with ovarian or breast cancer) [New Engl J Med 2017;377:1409-1412, N Engl J Med 2012;366:1382-1392, N Eng J Med 2017;377:523-533].Here, a patient is presented with a molecular diagnosis of Lynch syndrome and with breast cancer. Yet the breast cancer showed proficient expression of the same MMR gene found to be mutated in her germline testing. The case underscores the importance of tumor testing for MMR and MSI and of not assuming that the tumor is related to the Lynch syndrome rather than being sporadic. This is particularly true in patients with cancers (e.g., breast cancer) whose association with Lynch syndrome is not well established.The case presented also underscores the importance of considering next-generation sequencing of the tumor when the therapies approved are based on a germline mutation being the predictive marker. For example, the FDA-approved use of the PARP inhibitor olaparib is for ovarian or breast cancers in patients harboring a BRCA germline mutation [N Engl J Med 2012;366:1382-1392, N Eng J Med 2017;377:523-533]. Yet patients with tumors lacking BRCA loss of heterozygosity (LOH) or lacking other evidence of probable loss of normal BRCA gene product expression might be less likely to benefit from PARP inhibitor therapy, because the efficacy of PARP inhibitor therapy in patients with germline BRCA mutations would likely be predicated upon BRCA LOH in their tumors. KEY POINTS: Cancers in patients with germline mutations may be sporadic and unrelated to the germline mutation.Lynch syndrome is due to a germline mutated mismatch repair (MMR) gene. Cancers resulting from the germline MMR gene mutation as the predisposing event would be expected to be MMR deficient (dMMR) and microsatellite instability high (MSI-H). Sporadic cancers in patients with Lynch syndrome would be expected to be MMR proficient or microsatellite stable.Pembrolizumab is only approved for solid tumors demonstrating dMMR/MSI-H. Thus, whether the cancer tissue of origin is clearly associated with Lynch syndrome or not yet clearly established as a Lynch syndrome-related cancer (e.g., breast cancer), establishing the tumor to be dMMR/MSI-H is necessary to predict possible benefit and endorse the use of pembrolizumab.Ovarian cancers that develop in BRCA germline mutation carriers are so often related to the inherited mutated BRCA as the predisposing factor that testing the tumor for the footprint of BRCA-related ovarian cancer (BRCA loss of heterozygosity) is not necessary for use of the PARP inhibitor therapy olaparib. Future studies that include tumor evaluation for normal BRCA expression or surrogates of normal BRCA gene product expression might help determine which patients harboring a germline BRCA mutation are most likely to benefit from PARP inhibitor therapy.

Correlating Ki67 and other prognostic markers with Oncotype DX recurrence score in early estrogen receptor-positive breast cancer.

Decisions regarding adjuvant chemotherapy for early breast cancer are complex. Ki67 is increasingly used, in conjunction with conventional prognostic markers, to help decide the use of adjuvant chemotherapy for early breast cancer. Ki67 has been proposed as an economical alternative to Oncotype DX recurrence score (RS), which is a validated prognostic marker for disease recurrence and predictive marker for benefit from chemotherapy. This study aimed to determine in patients where conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy, whether Ki67 could be a substitute for RS. We reviewed all cases of luminal-type node-negative early breast cancer (T1-2, N0-1mi, M0, estrogen receptor positive, HER2 negative) referred for Oncotype DX testing by the multidisciplinary team at an Australian tertiary private hospital from 14th December 2006 to 31st December 2013, when conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy. RS was correlated with Ki67, along with other conventional prognostic markers including tumor size, grade, mitotic rate and lymphovascular invasion. Spearman's rank order correlation coefficient and Pearson product-moment correlation coefficient (r) were used for ordinal and continuous variables, respectively. A total of 58 patients were analyzed, median Ki67 was 15% (range 2-50%) and the median RS was 16 (range 3-65). There was no positive correlation between Ki67 and RS (r=0.01, P=0.93). No single conventional prognostic marker was shown to significantly correlate with RS, including tumor size (r=-0.02, P=0.88), grade (r=0.10, P=0.44), mitotic rate (r=-0.07, P=0.69) and lymphovascular invasion (r=-0.12, P=0.39). Ki67 and conventional prognostic markers do not correlate with Oncotype DX RS. In the setting where conventional prognostic markers do not show a clear indication for or against adjuvant chemotherapy as determined by consensus in a multidisciplinary team, Ki67 is not a substitute for Oncotype DX testing. RS may provide additional information to aid decision making for adjuvant chemotherapy.

Microarray-based tumor molecular profiling to direct choice of cisplatin plus S-1 or oxaliplatin plus S-1 for advanced gastric cancer: A multicentre, prospective, proof-of-concept phase 2 trial.

48 Background: Theoxaliplatin/S-1 (SOX) and cisplatin/S-1 (SP) regimens are interchangeably used in the management of advanced gastric cancer (AGC). We previously developed a classification tool using gene expression signatures which successfully stratified gastric cancer cell lines and primary tumour samples according to their sensitivity to SOX or SP ( Tan et al, Gastroenterology 2011). We now report the first prospective study to evaluate the feasibility and efficacy of using a genomic classifier to tailor treatment in this setting. Methods: Pts with histologically-confirmed locally-advanced, metastatic and recurrent GC were recruited from 3 centres in Singapore and South Korea. Tumours were analysed using the Affymetrix HG-U133 Plus 2.0 array and results were used to classify pts as G1 (oxaliplatin-sensitive), G2 (cisplatin-sensitive) and G3 (status unclear or gene expression not available). G1 and G2 pts were matched to SOX and SP regimens respectively, while G3 pts were assigned SOX. The primary endpoint was best overall response; secondary endpoints were turnaround time and biomarker analyses. Results: Between July 2, 2010, and Apr 2, 2015, we screened 85 AGC pts. 74 pts received at least 1 cycle of treatment and were evaluable for analysis. Median turnaround time was 7 working days (IQR, 5–9). The misclassification rate was 6%. After an initial 30 pts in the G1 subgroup were treated with SOX, subsequent pts ( N = 13) classified as G1 received the SP regimen. The ORR were 44.8%, 8.3%, 26.7% and 55.6% for G1 SOX, G1 SP, G2 SP ( N = 19), G3 SOX ( N = 12) respectively; and was higher in G1 pts treated with SOX compared with SP ( P = 0.033). Post hoc genomic reclassification based on Lei et al (Gastroenterology 2013) confirmed the utility of the metabolic subtype as a predictive marker of benefit from chemotherapy (log rank P value for PFS = 0.004). Conclusions: This bench-to-bedside effort establishes that molecular profiling to direct choice of conventional chemotherapy for AGC is possible within a reasonable timeframe. The clinical utility of our genomic classifiers in question are promising but warrant further investigation. Clinical trial information: NCT01100801.

Treatment-free interval (TFI) after first-line therapy as a prognostic and predictive factor in malignant pleural mesothelioma (MPM): Findings from the NGR015 phase III trial with NGR-hTNF plus best investigator choice (BIC) versus placebo plus BIC.

7557 Background: Historically, the TFI (time from end of first-line to start of second-line therapy) has been reported as a prognostic factor and predictive marker of benefit of next treatment line...

Analysis and significance of c-MET expression in adenoid cystic carcinoma of the salivary gland

Adenoid cystic carcinoma (ACC), a rare salivary gland malignancy, is a histogenetic, morphologic, and clinical heterogeneous disease. Extensive efforts have been made to characterize molecular events associated with these tumors, including the identification of prognostic and predictive biomarkers. Increased copy number gain and amplification of c-Met, the cell surface receptor for hepatocyte growth factor, has been shown to enhance tumor growth and invasiveness and promote metastasis in certain tumor types. In this study, we evaluated the expression of c-Met by immunohistochemistry (IHC) in a large cohort of salivary gland ACCs and examined its clinicopathologic implications. Archival formalin-fixed paraffin-embedded blocks from 200 ACC patients were used in this study. Pathologic patterns and phenotypic expression of c-Met were recorded and compared with clinical factors including gender, age, disease stage at diagnosis, and clinical outcomes. Correlations between c-MET expression and clinical characteristics were assessed by Pearson's chi-square test or by the 2-tailed Fisher exact test. Curves describing overall survival were generated by Kaplan-Meier product limit method. Strong c-MET expression was seen in inner ductal and outer myoepithelial cells in 53.2% of the cases. There was no correlation between c-Met overexpression and clinicopathologic parameters or patient's overall survival ( p = .94074). In conclusion, c-MET expression is high in a significant subgroup of ACC patients. While c-MET expression is not a prognostic factor in ACC, its role as a predictive marker of benefit from MET inhibitors deserves further investigation.

P04.10 * PREDICTIVE VALUE OF MGMT PROMOTER METHYLATION QUANTITATIVE ASSESSMENT IN GLIOBLASTOMA, WHICH OPTIMAL CUT-POINT?

BACKGROUND: The methylation in the promoter region of the MGMT gene encoding the DNA repair protein O6-methyl guanine-DNA methyl transferase is a predictive marker for benefit from alkylating agent therapy and a prognostic factor in glioblastoma. Pyrosequencing-based assessement of MGMT promoter status is of particularly interest, but analytical methods and cut-points may varied from one center to another. We intend to establish a correlation between quantitative methylation of MGMT promoter values and overall survival (OS) or progression-free survival (PFS). METHODS: The clinical and biological data of 159 newly diagnosed glioblastoma recruited in Lille University Hospital between 2008 and 2011 were retrospectively collected. For the patients, the methylation status has been assessed by pyrosequencing on 5 CpG islands. Statistical analyses were performed using SAS software V9.3. RESULTS: Median age of the patients was 61 years. Sixty three patients were male. Of 159 patients, 156 underwent a surgery (40,4% of complete resection), 3 patients were diagnosed only by biopsies. 123 received concomitant radiotherapy and temozolomide and adjuvant temozolomide. The median PFS and the median OS were 9,9 and 15,9. The most significant cut-off methylation determined on 5 sites mean methylaion value was 12% for both predictive and pronostic evaluations. Site 1 methylation status was the best predictive value for both PFS and OS compared to the other CpG islands. On this site 1, a >3% methylation status was a significant predictive factor for reponse to standard treatment for PFS and a >25% site 1 methylation status was a strong pronostic factor for 2 years survival (OS) (47%). CONCLUSIONS: Even a low MGMT methylation (>3%) status on selected CpG site can already be a predictive factor for response to treatment in glioblastoma and allow us to reduce the cut-off values. Highest methylations status are correlated with the longest overall survival and therefore confirm the pronostic value of MGMT methylation. Establishing correlation between clinical data and biological assessment, such as pyrosequencing providing quantitative values for each CpG, would allow to lower and precise useful cut-points and to chose analysed site for a better predictive and pronostic significativity.

Tilting the Balance of Dose Modification for Oral Anticancer Drugs?

Tilting the Balance of Dose Modification for Oral Anticancer Drugs?

Biomarkers and Response to Bevacizumab—Response

We wish to thank Cremolini and colleagues for their interesting letter that highlights their previous finding that VEGFR-2 may be a predictive marker for benefit from bevacizumab therapy. Their data are derived from the setting of postprogression bevacizumab in advanced colorectal cancer, and there

Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin)-treated patients with metastatic pancreatic cancer: The randomized phase II PAN1 study.

228 Background: GEM-based treatment is a standard treatment for metastatic pancreas cancer. Monotherapy efficacy is only modest, and outcomes are improved by combination treatment or the non-GEM FOLFIRINOX triplet. There is a need for biomarkers to select between these divergent options. hENT1 is a potential predictive marker of benefit from GEM, but conflicting results have been observed in studies that have evaluated resected and metastatic pancreatic cancer. This principal objective of this study was to evaluate hENT1 prospectively as a predictive marker in GEM and non-GEM treated patients. Methods: Patients with previously untreated metastatic pancreatic adenocarcinoma and tumour tissue available for hENT1 testing were randomized between GEM (1,000 mg/m2 D1, 8, 15 Q4w) or FOLFOX (oxaliplatin 85 mg/m2, 5-fluorouracil (5FU) 400 mg/m2, leucovorin 400 mg/m2 D1 and 5FU 2,400 mg/m2over 46 hours D1-3) until disease progression or unacceptable toxicity. Tumor samples were tested prospectively for hENT1 by immunohistochemistry. The primary endpoint was progression-free survival (PFS). Results: The study was open from July 2011 to February 2013, but closed after 16 of the planned 80 patients were enrolled. 1 patient who died before treatment was excluded from the outcome analysis. 7/16 patients were hENT1 high (43.8%, 95%CI 23.1-66.8%). In the GEM arm (n=7), the 4 who were hENT1 high had longer PFS and overall survivals (OS) than those who were hENT1 low (median PFS 5.7 vs. 1.8 months; median OS 13.9 vs. 3.5 months), whereas outcomes were similar with FOLFOX for both hENT1 groups. There were no unexpected adverse events. Conclusions: This prospective study showed a longer survival in those patients with high hENT1 treated with GEM. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. Clinical trial information: ACTRN12610001047088.[Table: see text]

Glioblastoma multiforme: A bigger challenge in resource-limited countries

Glioblastoma multiform (GBM), the most common and the most aggressive brain tumor in older adults, once diagnosed kills majority of the patients within the first year despite aggressive surgical resection and high doses of radiation therapy (RT). Initially, nitrosureas such as lomustine were the main chemotherapeutic agents used although they only showed modest success.[1] Since Stupp et al. published their breakthrough findings in 2002, the accepted standard therapy worldwide for GBM has been concurrent fractionated RT (60 Gy, 2 Gy × 5 d/wk for 6 weeks) with temozolamide followed by maintenance therapy with temozolamide prolonged the survival with minimal toxicity.[2] Investigators later found that a higher initial Karnofsky performance Score and O6-methylguanine–DNA methyltransferase (MGMT) methylation were associated with better prognosis and longer survival.[3,4] In this issue of the Journal, Kumar et al. reported a series consisting of 439 patients with GBM over a period of nine years in their institution where healthcare was not equally accessible or affordable.[5] They divided the group into two groups: Those whose Karnofsky Performance Score was <70 and received RT dose of 30-35 Gy in 10-15 fractions and those with Karnofsky Performance Score ≥70 who received conventional RT dose of 60 Gy in 30 fractions once daily for five days a week with or without adjuvant chemotherapy with temozolamide or lomustine. The authors found that the two-year survival rates were 2.2% and 8.2% with median survivals of 6.3 and 7.9 months, respectively, (P = 0.0010). They also found that the main reason for not initiating or discontinuation of RT or adjuvant chemotherapy with either temozolamide or lomustine was secondary to cost and not due to toxicity. The study was limited by its retrospective nature and grouping of patients based solely on performance status with those in poor performance status plus larger tumor burden selectively receiving lower RT doses, thus faring worse. The challenges the authors faced as with many similar resource-limited countries was being unable to provide what is the known best standard of care for their patients. The authors urged that in patients with poor performance status, hypofractionated RT schedule may be considered. In a recent publication in Lancet Oncology by Malstrom et al. consisting of 291 patients with GBM, the investigators found that the standard fractionated RT (60 Gy administered in 2 Gy fractions over 6 weeks) was associated with poor outcomes, especially in patients older than 70 years. In their study, the median survival in the intent-to-treat population was 8.3 months for temozolomide, 7.5 months for hypofractionated radiation, and 6 months for standard radiation. The authors concluded that both temozolomide and hypofractionated radiotherapy as defined by (34 Gy administered in 3·4 Gy fractions over 2 weeks) should be considered as standard treatment options in elderly patients with glioblastoma.[6] Similarly, Lo et al. highlighted their findings during the 2011 American Society of Clinical Oncology annual meeting and concluded hypofractionated radiotherapy to be a safe and effective treatment for glioblastoma, especially in those patients who are elderly or have poor performance status.[7] In resource-limited countries with high patient volume, late disease presentation, and high treatment abandonment, we are far from being able to provide testing on MGMT promoter methylation status as a useful predictive marker for benefit from temozolomide or various other targeted anti-angiogenic therapies. Would it then be more desirable to consider hypofractionated RT as the standard therapy for those diagnosed with GBM? As Kumar et al. have revealed, hypofractionated RT is well-tolerated, and it can also reduce the overall treatment time without negative effects on survival compared with conventional fractionation.

Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate resistant prostate cancer (CRPC).

5077 Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase II study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of &gt; 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]

Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance).

11011 Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI +/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR=0.64, p=0.002) and EREG (HR=0.89, p=0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo + C: HR=1.15; chemo only: HR=0.48, interaction p=0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo + C: HR=0.91; chemo only: HR=1.57, interaction p=0.026) and MT tumors (chemo + C: HR=0.80; chemo only: HR=1.29, p=0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.

Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus erlotinib.

4014 Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) &gt; 6 weeks, 10 with SD &gt; 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline &gt; 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.

Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate-resistant prostate cancer (CRPC).

64 Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase 2 study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of ≥ 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab

BackgroundThe vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens.MethodsFormalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death.ResultsAmong the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald’s p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald’s p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death.ConclusionsTOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial

Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.