Initiation Of First-line Therapy Research Articles

EGFR gene mutation and epithelial to mensenchymal transition (EMT) markers in advanced NSCLC patients treated with erlotinib.

e18117 Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition (EMT). Previous work in a clinically enriched non-small cell lung cancer (NSCLC) population suggested low probability of an EGFR activating gene mutation in the absence of TTF-1 positivity (Somaiah ASCO 2011). This study's goal was to validate the relationship of TTF-1 and other immunohistochemical (IHC) markers of EMT to the presence of an EGFR activating gene mutation in a diverse group of NSCLC patients treated with erlotinib. Methods: Patients receiving erlotinib at two midwest institutions were retrospectively analyzed by IHC for TTF-1 (Greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining considered positive) and for PTEN, Ecadherin,vimentin, beta catinin, and snail (frequency(0-4) times intensity(0-4)). Exon 19 and L858R mutations were detectedusing single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR)).Fisher’s exact testand logistic regression wereused to correlate TTF-1(positive or negative) and the remaining EMT markers with the presence of EGFR mutation. Results: 216 patients were analyzed for EGFR activating gene mutations: 15% squamous, 80% smokers. EGFR mutation was found in 11.6% of cases. TTF-1 was present in 8% of squamous cell patients and 71% of adenocarcinoma patients. TTF-1 correlated with prolonged progression free survival (log rank p=.004). TTF-1 positivity was strongly correlated with the presence of mutation (p=.0006, negative predictive value=97.7%). Increasing Ecadherin and increasing PTEN expression by IHC correlated with the presence of EGFR gene mutation when measured on continuum (p=.006 and p=.04, respectively). Conclusions: Though retrospective, our work confirms the negative predictive value of TTF-1 for an EGFR activating gene mutation in a NSCLC cohort representative of a North American population.Though high PTEN and Ecadherin expression also correlated with EGFR mutation, TTF-1 positivity may be a more straight-forward marker that can select patients who should be screened for the mutation prior to initiation of first line therapy.

Abstract 2387: Analysis of the expression of stemness and epithelial-to-mesenchymal transition markers in circulating tumor cells of patients with breast cancer

Abstract Introduction: Circulating tumor cells (CTCs) have been identified in peripheral blood (PB) of patients with breast cancer and their presence has been associated with poor disease outcome. Cancer is considered to be driven by cancer stem cells (CSCs) whose connection to metastatic spread remains incompletely understood. In addition, Epithelial-to-Mesenchymal transition (EMT) has been proposed as an essential process in the metastatic cascade. A link between stem cell-like properties and the ability of cancer cells to undergo EMT has recently been suggested. In breast cancer, ALDH1 and Twist have been proposed among others as stemness and EMT markers, respectively. The expression of these markers in CTCs could be an important determinant of increased metastatic risk and resistance to conventional therapies. In the present study we aimed to investigate the co-expression of ALDH1 and Twist in CTCs from patients with metastatic breast cancer, at the single cell level. Patients and Methods: PBMCs’ cytospins were prepared from PB obtained from 150 patients with metastatic breast cancer, prior to the initiation of first-line therapy. Triple immunofluorescence experiments were performed in patients’ samples using the cytokeratin anti-mouse antibody (A45-B/B3) conjugated with Alexa 488 by Zenon technology along with ALDH1 anti-rabbit and Twist anti-mouse antibodies. A total of 500.000 PBMCs per patient were analyzed by the use of ARIOL system. Results: CTCs were identified in 70 out of 150 (47%) patients. A total of 428 CTCs were detected with a median of 2 CTCs per patient (range: 1-27). All patients had detectable ALDH1 expressing CTCs, whereas high ALDH1 expression levels were confirmed in 63% of the total number of CTCs identified. In addition, Twist expression in CTCs was evident in 99% of patients and in 93% of the total CTCs detected. Concerning the co-expression of these molecules in CTCs, the most abundant phenotype was ALDH1high Twist +, identified in 62% of CTCs, with a median expression of 58% per patient. Furthermore, no CTCs expressing the phenotype ALDH1- Twist + were detected in any patient. The correlation between Twist expression and high ALDH1 expression levels in CTCs was statistically significant (p=0.005). Conclusions: The above results demonstrate that stemness and EMT markers are co-expressed in the majority of CTCs from patients with metastatic breast cancer. This observation supports the hypothesis that there is a link between stem-cell like features and EMT in cancer cells. In addition, the co-expression of stemness and EMT markers in CTCs could be related to their metastatic potential and might help to further refine prognosis of patients with breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2387. doi:1538-7445.AM2012-2387

Circulating Angiogenic Cytokines Are Elevated in Patients with Smoldering Myeloma; Implications Into Disease Biology

Abstract 5059Angiogenesis is a critical step in the evolution of carcinogenesis in solid tumors and hematologic malignancies and is considered to be an early event in tumorigenesis. Multiple myeloma (MM) is a hematologic malignancy in which a preceding monoclonal gammopathy (MGUS) is considered a precursor. Asymptomatic/smoldering MM (SMM) is associated with a substantial risk of progression to MM and according to current recommendations these patients should be followed without therapy. Thus evolution from MGUS to SMM and to symptomatic myeloma is now considered as the model describing the natural history of the disease. In order to study the role and evolution of circulating angiogenesis related cytokines, we studied their levels in patients with MGUS, asymptomatic MM and symptomatic MM, before the initiation of first line therapy. We also studied possible associations of these cytokines with features of the disease in patients with SMM that could help identify possible markers of early evolution.We measured serum levels of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin (angp)-1 and -2, using standard ELISA methodology (R&D Systems, Minneapolis, MN, USA). The definition of MGUS, SMM and symptomatic MM was based on the published IMWG criteria. All above cytokines were also measured in 21 individuals with MGUS, in 174 newly diagnosed, untreated MM patients (31 with SMM) and in 44 age- and gender-matched healthy controls.We focused our analysis on patients with SMM. The median age was 63.5 years (range 40–83 years) and 55% were males. The median bone marrow infiltration in trephine biopsy was 20% (range: 12%-75%). Sixty-one per cent had IgG, 29% had IgA isotype while 3% had light chain only myeloma and 6% had biclonal myeloma.The median (range) serum levels for VEGF were 406.5 pg/ml (186.3–797.6 pg/ml), for angp-1 were 31064 pg/ml (18220–50856 pg/ml), for angp-2 were 1434 pg/ml (486.1–4004.5 pg/ml), for angp-1 to angp-2 ratio were 20.8 (6.5–78.1), for angiogenin were 262732.6 pg/ml (138670–1003040 pg/ml) and for bFGF were 12.082 pg/ml (non-detected to 123.37 pg/ml). There were no significant correlations of the levels of angiogenesis related cytokines with serum beta-2 microglobulin levels, the levels of the monoclonal protein, IgA versus IgG isotype, serum LDH levels or age. Patients with extensive bone marrow infiltration (≥60%) had significantly higher levels of ang-2 (p=0.017) and significantly lower angp-1/angp-2 ratio (p=0.004) compared to all others. Compared to healthy controls, patients with SMM had higher levels of angp-1 (p=0.05) and angp-2 (p=0.03) but their respective ratio was not significantly different (p=0.272). Serum levels of VEGF were significantly higher in SMM patients than in controls (mean 429 pg/ml vs. 196 pg/ml, p<0.001). Similarly serum levels of angiogenin were significantly higher in SMM (mean 304028 pg/ml vs 190245 pg/ml, p<0.001). When patients with SMM compared to MGUS patients, there were no significant differences for any of the studied angiogenesis related cytokines. Compared to patients with symptomatic MM, patients with SMM had higher levels of angp-1 (p<0.001) and lower level of angp-2 (p<0.001) resulting in a significantly lower angp-1/angp-2 ratio, indicating a switch to increased vessel-formation activity, while the levels of VEGF were similar.The above results indicate that early in the evolution of the disease (MGUS to SMM to Symptomatic MM) there is an angiogenic switch which is manifested by an increase in the levels of angiogenic cytokines that promote neovasculogenesis (such as VEGF, angp-2 and angiogenin) and a gradual suppression of cytokines that balance their effects (such as angp-1). A possible prognostic significance of the circulating levels of angiogenic cytokines in patients with SMM that could help identify patients at higher risk for progression to symptomatic MM needs further study. Disclosures:No relevant conflicts of interest to declare.

The association of clinical outcome to front-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC) patients (Pts).

4555 Background: In mRCC pts who fail first-line VEGF-targeted therapy, there are no available randomized data comparing active drugs. Currently, many clinicians choose a second-line VEGF-targeted therapy based on the type of response to first-line VEGF therapy, although no data exists to support this practice. Methods: Pts treated with targeted therapy in the International mRCC Database Consortium were examined to identify pts who received a second-line VEGF-targeted therapy after failure of a different first-line VEGF-targeted therapy. Response rates and progression-free survival (PFS) were compared in the first- and second-line settings. Results: Of 1,602 total database pts, 464 pts received second-line VEGF-targeted therapy (sunitinib 37%, sorafenib 51%, axitinib 2%, bevacizumab 7%, pazopanib 3%) after failure of first-line VEGF-targeted therapy (sunitinib 54%, sorafenib 33%, bevacizumab 13%). The median overall survival from initiation of first-line therapy for pts who received second-line therapy wa...

Can ISSWM Be Used for Making Treatment Decisions?

Using age, hemoglobin level, platelet count, serum β2-microglobulin and monoclonal protein concentrations, the International Scoring System for WM (ISSWM) has been specifically designed for predicting survival after the initiation of first-line therapy. Five-year survival rates of low-, intermediate-, and high-risk patients were 87%, 68%, and 36%, respectively. The aim of the present review was to assess the applicability of this statistical model for making treatment decision in clinical practice, despite the difficulties posed by the characteristics of this rare disease. Finally, we propose that the distribution of ISSWM subgroups should be reported in any treatment reports.

Outcomes After Multiple Lines of Chemotherapy for Platinum-Resistant Epithelial Cancers of the Ovary, Peritoneum, and Fallopian Tube

Platinum-resistant and refractory cancers of the ovary, fallopian tube, and peritoneum have a poor prognosis, yet in some cases, they can respond to multiple lines of chemotherapy. Uncertainty remains over optimal drug choice and when therapeutic focus should be switched from active therapy to supportive care. A retrospective case note review was performed on 274 women treated for platinum-resistant/refractory ovarian, fallopian tube, or peritoneal carcinoma at the Christie Hospital between 2004 and 2008. Baseline data at onset of platinum resistance and outcomes from subsequent lines of therapy were recorded. A total of 689 lines of therapy were administered with a median overall survival from initiation of first-line therapy for platinum-resistant disease of 61 weeks. Twenty-eight percent of women commenced cytotoxic therapy in the last 3 months of life. Treatment efficacy declined rapidly with successive lines of therapy particularly if disease progression occurred during first-line therapy. Factors independently associated with worse overall survival at recognition of platinum resistance were performance status, presence of stage IV disease, elevated cancer antigen 125, and platinum-refractory disease. A significant proportion of women who were treated received therapy within the last few months of life with little clinical benefit. Disease progression on 2 consecutive lines of therapy should be used as a guide to discontinue cytotoxic treatment. A subset of patients with poor prognosis at the onset of platinum resistance, who may have little gain from anticancer treatment, can be identified.

Tumor burden status evaluated by computed tomography scan is of prognostic importance in patients with chronic lymphocytic leukemia

It has been discussed if computed tomography (CT) scan is necessary to perform or not, to provide prognostic information in patients with chronic lymphocytic leukemia. In the current National Institute Chronic lymphocytic leukemia Working Group (NCI-WG) guidelines, CT scan is not recommended outside clinical trials but states that further trials are warranted. Computed tomography scan of lymphadenopathy and/or splenomegaly was detected in totally 74 patients, leading to a modified Rai stage in 9 (12%) patients (from stage I to II). Using CT, 19 patients fulfilled the GELF high tumor burden criteria and/or one bulky node > or =7 cm. CT showed splenomegaly in totally 54 (73%) patients, of which 22 (41%) cases had not had been detected during clinical examination. According to the NCI response criteria for chronic lymphocytic leukemia (CLL), 15 (22%) patients showed a CR and 43 (62%) a PR, while when including CT findings, 12 (17%) fulfilled criteria for CR and 41 (59%) for PR. Patients with a high lymphadenopathy tumor burden according to the GELF criteria at the time of initiation of first-line therapy had a shorter time from response to next therapy or death, 12 months compared with 35 months for patients with less advanced lymphadenopathy (P = 0.002). There was also a trend for a shorter overall survival in the high tumor burden group, 58 months compared to 75 months (P = 0.098). Massive splenomegaly was related to a shorter therapy-free as well as overall survival. In our opinion, clinical examination is not sufficient for evaluation of abdominal lymphnodes and spleen in patients with therapy requiring CLL.

First-line trastuzumab utilization: Patterns of care and progression in the community setting

e12009 Background: This study describes patterns of care and outcomes in metastatic breast cancer (MBC) patients treated with trastuzumab (T) within the US Oncology network. Methods: This retrospective study utilized data from US Oncology's iKnowMed EMR system. HER-2 (+) MBC patients who initiated a first-line regimen containing T between January 1, 2006 and July 31, 2007, were identified. Patients were divided into three treatment cohorts: A) those who discontinued T prior to disease progression; B) those who continued T following discontinuation of chemotherapy prior to progression; and C) those who received T monotherapy. Patients were followed through October 31, 2008, to measure treatment duration and observe progression (as defined as escalation to second-line therapy). The Kaplan Meier method/log-rank test were used to estimate and compare progression free survival (PFS) across cohorts. Results: We identified 139 patients receiving first-line therapy including T. The median age was 58 years and 84 patients were ER and/or PR (+). The top 5 chemotherapy regimens included T plus: paclitaxel (n = 14); docetaxel (n = 14); vinorelbine (n = 14); carboplatin/paclitaxel (n = 12); carboplatin/docetaxel (n = 7 pts). Twenty-one (15%) patients were in cohort A, 55 (40%) were in cohort B, and 63 (45%) were in cohort C. Overall, the median duration of first-line T use was 281 days (mean = 287; range = 1–862). Following the initiation of first-line therapy, a total of 56 (40%) patients progressed (median follow up = 15 months). Following progression, 22 (39%) patients received second-line regimens containing T. The overall median PFS was 17.4 months (mean = 18.6). Patients in cohort A (n = 15) had significantly shorter PFS versus patients in cohort B/C (median 3.9 and 19.6 months, respectively; p &lt; 0.001). Conclusions: In this observational study within the outpatient community setting, persistent first-line T use for MBC was associated with delayed disease progression. Future research should evaluate the causal relationship of this association. In addition, a more comprehensive evaluation should be conducted of therapies prescribed concomitant to T for patients treated with T “monotherapy.” [Table: see text]

SDF1/CXCL12 (−801GA) polymorphism is a prognostic factor after treatment initiation in Waldenstrom macroglobulinemia

The interaction of the chemokine CXCL12 with CXCR4 regulates homing of tumoral cells in bone marrow in Waldenstrom macroglobulinemia (WM). We assessed the distribution and the clinical influence of the CXCL12 (−801GA) polymorphism using PCR RFLP in a series of 114 WM patients. CXCL12 (−801AA) genotype was more frequent in WM patients compared with control subjects ( p = 0.01). On the other hand, CXCL12 (−801GG) patients had a shorter median survival after initiation of first line therapy than remaining patients ( p = 0.01). In conclusion, the CXCL12 (−801GA) polymorphism may either be associated with a high incidence of WM or influence clinical outcome.

Risk Factors for Response after Initial Therapy for Acute Graft-Versus-Host-Disease (aGVHD).

Introduction: Acute GVHD remains the most important early complication and limitation to allogeneic hematopoietic stem cell transplantation (HSCT). Although far from optimal, corticosteroids remain initial standard therapy with an overall response rate of 50%. Steroid resistant patients have a dismal prognosis, with mortality rates reaching 90%.Objective: To identify the subgroup of patients that would not benefit from initial therapy with corticosteroids. Thus, accrual of these patients into clinical studies would be mandatory.Methods: Retrospective evaluation of all (N= 287) patients who developed biopsy proven aGVHD after allogeneic HSCT at the University of Texas M. D. Anderson Cancer Center from 1998 through 2002. All patients received initial therapy for aGVHD with methylprednisolone. Prognostic factors for response (CR/PR) to initial therapy with corticosteroids were evaluated using logistic regression analysis including age, gender, donor/patient sex mismatch (F/M), donor type, cell type, intensity of conditioning regimen, diagnosis, disease status at transplant, number of prior chemotherapy regimens, number of prior autologous HSCT, CD34+ cell dose infused, time of onset of aGVHD and grade at initiation of first line therapy.Results: At the time of first line therapy, 89/287 patients (31%) had grade I aGVHD, 141 (49%) had grade II, and 57 (20%) had grade III–IV. Overall response to first line therapy was 56% and was comparable between patients with grade I and II aGVHD. Grade III–IV aGVHD (CR/PR 39% vs. 60%, p=0.003) and hyperacute GVHD (occurring by day +14) (CR/PR 42% vs. 61%, p=0.007) were the most significant prognostic factors for failure. Sex mismatch was associated with significantly lower response rate in patients with grade III–IV (CR/PR 12% vs. 49%, p=0.02) but not in patients with grade I–II (CR/PR 61% vs. 60%, p=0.9). Failure to respond to first line therapy was the most significant predictor of non-relapse mortality at one and two years after initiation of first line therapy (p<0.001) for all GVHD grades.Conclusions: Hyperacute GVHD and sex mismatch are significant predictors of response to first line therapy. Response to first line therapy has a strong and independent effect on survival. These factors should be integrated in prognostic scoring systems of aGVHD, which would allow identification of patients who would not benefit from standard therapeutic approaches.Response To First Line TherapyOverall (N=287)n%CR/PRp valueGrade at First LineI8965%ReferenceII14157%0.2III/IV5739%0.003Grade I/II (N=230)Grade III/IV(N=57)n, %CR/PRp valuen, %CR/PRp valueHyperacute GVHDYes7342%60, 48%13, 15%No21461%0.007170, 65%0.0344, 45%0.05Donor/Patient sex mismatchYes7351%57, 61%16, 12%No21458%0.3173, 60%0.941, 49%0.02CR: complete remission, PR: partial remission

Circulating Tumor Cells: A Novel Prognostic Factor for Newly Diagnosed Metastatic Breast Cancer

Metastatic breast cancer (MBC) is incurable; its treatment is palliative. We investigated whether the presence of circulating tumor cells (CTCs) predicts treatment efficacy, progression-free survival (PFS), and overall survival (OS) in patients with newly diagnosed MBC who were about to start first-line therapy. One hundred seventy-seven patients with measurable MBC were enrolled onto a prospective study. Eighty-three of the 177 patients were entering first-line treatment, and these patients are the focus of this analysis. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and monthly thereafter for up to 6 months were isolated and enumerated using immunomagnetics. The mean (+/- standard deviation) follow-up time was 11.1 +/- 4.4 months (median, 12.2 months). Forty-three patients (52%) had > or = five CTCs at baseline. The median PFS was 7.2 months (95% CI, 4.9 to 9.4 months), and the median OS was more than 18 months. Patients with > or = five CTCs at baseline and at first follow-up (4 weeks) had a worse prognosis than patients with less than five CTCs (baseline: median PFS, 4.9 v 9.5 months, respectively; log-rank, P = .0014; median OS, 14.2 v > 18 months, respectively; log-rank, P = .0048; first follow-up: median PFS, 2.1 v 8.9 months, respectively; log-rank, P = .0070; median OS, 11.1 v > 18 months, respectively; log-rank, P = .0029). CTCs before and after the initiation of therapy were strong, independent prognostic factors. Detection of CTCs before initiation of first-line therapy in patients with MBC is highly predictive of PFS and OS. This technology can aid in appropriate patient stratification and design of tailored treatments.