Heterogeneity Of Tumor Biology Research Articles

Abstract 2496: Molecular characterization of stage III colon cancer patients with recurrence after adjuvant chemotherapy

Abstract Introduction: Patients with stage III colon cancer are routinely treated with resection followed by adjuvant chemotherapy (ACT) with a fluoropyrimidine and oxaliplatin. This one-size-fits-all approach does not account for heterogeneity in tumor biology and fails to cure ~30% of patients, highlighting the urgency for biomarkers to better understand and predict resistance to ACT or to offer alternative targeted treatment. Aim: To identify molecular characteristics predictive of resistance to standard ACT in stage III colon cancer. Methods: Patients with resected stage III colon cancer who received ACT (93% CAPOX, 7% CAP) were selected from the Prospective Dutch Colorectal Cancer cohort (PLCRC). RNA exome capture sequencing was performed on resected FFPE tumor tissue to compare differential gene expression, hallmark pathway enrichment, immune cell deconvolution and consensus molecular subtypes (CMS) between patients with versus without recurrence after surgery and ACT. Postsurgery circulating tumor DNA (ctDNA) detected in PLCRC-PROVENC3 (separate abstract) was used to select a subgroup with minimal residual disease (MRD) postsurgery, as sensitivity analysis of patients with recurrence despite ACT (chemoresistant) versus curation by ACT (chemosensitive). Results: For 264 out of 278 patients (95%), tumor-derived RNA sequencing libraries were of sufficient quality. 67 patients (25%) with recurrence (median after 13 months [IQR 7-23]) were compared to 178 patients with at least 2 year recurrence-free follow-up (median 42 months [IQR 30-53]). A total of 320 genes were differentially expressed between patients with versus without recurrence. Genesets defining epithelial-mesenchymal transition (p = 0.002) and angiogenesis (p < 0.001) were enriched in the primary tumor of patients with recurrence, in part explained by the estimated larger fraction of stroma (Wilcoxon effect size r 0.18, p < 0.001) and cancer-associated fibroblasts (CAFs) (r 0.19, p = 0.003). In contrast, the fraction of CD4+ T cells was lower (r 0.14, p = 0.001). Consistently, CMS4 was found more frequently in tumors from patients with versus without recurrence (57% versus 34%, p < 0.001). Of the subgroup with ctDNA-based MRD postsurgery (26 out of 171 assessed patients), 19 patients (73%) with recurrence (median after 12 months [IQR 7-17]) were compared to 7 patients without recurrence (minimum follow-up 32 months). This sensitivity analysis showed similar trends in pathways, immune cells and CMS as the main analysis, with a more pronounced effect size for CAFs (r 0.27). Conclusion: Stage III colon tumors of patients who experience recurrence after resection and ACT are enriched for stroma and CAFs, while displaying less CD4+ T cells. The observed trends are sustained in the patients with MRD postsurgery. These findings may help to better predict resistance to standard ACT and elucidate targets for alternative personalized treatment. Citation Format: Ingrid Franken, Steven Ketelaars, Carmen Rubio-Alarcón, Sietske van Nassau, Suzanna Schraa, Gerrit Meijer, Mark Sausen, Miriam Koopman, Geraldine Vink, Sanne Abeln, Remond Fijneman, Jeanine Roodhart, on behalf of the PLCRC-MEDOCC group. Molecular characterization of stage III colon cancer patients with recurrence after adjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2496.

Differential response to neoadjuvant endocrine therapy for Black/African American and White women in NCDB

PurposeCompared to White women, there are higher mortality rates in Black/African American (BAA) women with hormone receptor-positive breast cancer (HR + BC) which may be partially due to differences in treatment resistance. We assessed factors associated with response to neoadjuvant endocrine therapy (NET).MethodsThe National Cancer Database (NCDB) was queried for women with clinical stage I–III HR + BC diagnosed 2006–2017 and treated with NET. Univariate and multivariate analyses described associations between the sample, duration of NET, and subsequent treatment response, defined by changes between clinical and pathological staging.ResultsThe analytic sample included 9864 White and 1090 BAA women. Compared to White women, BAA women were younger, had more co-morbidities, were higher stage at presentation, and more likely to have > 24 weeks of NET. After excluding those with unknown pT/N/M, 3521 White and 365 BAA women were evaluated for NET response. On multivariate analyses, controlling for age, stage, histology, HR positivity, and duration of NET, BAA women were more likely to downstage to pT0/Tis (OR 3.0, CI 1.2–7.1) and upstage to Stage IV (OR 2.4, CI 1.002–5.6). None of the women downstaged to pT0/Tis presented with clinical stage III disease; only 2 of the women upstaged to Stage IV disease presented with clinical Stage I disease.ConclusionIndependent of NET duration and clinical stage at presentation, BAA women were more likely to experience both complete tumor response and progression to metastatic disease. These results suggest significant heterogeneity in tumor biology and warrant a more nuanced therapeutic approach to HR + BC.

Commentary: Nanoparticle-Based Chemotherapy Delivery and Potential Health Risks: Prospects for Effective Clinical Translation.

With recent advancements, chemotherapy is one of the most prevalent regimens for cancer treatment. However, the heterogeneity of tumor biology and healthy cell-damaging potential of chemotherapy remain challenges. As a solution, nanoparticle-based delivery is advancing. Besides its promising potential, effective clinical translation and commercialization of nanoparticle-based chemotherapy should get attention to ensure the absence of potential health risks. Specifically, the permeability potential of nanoparticles across biological barriers can lead to drug accumulation in vital organs and produce harm. Therefore, for effective design and clinical application of next-generation nanomedicine, pharmaceutical formulation scientists should conduct intensive studies. They involve studying the properties of drug-loaded nanoparticles in the microenvironment of the target site and the impact of interspecies differences using quantitative and mechanistic studies. It creates a comprehensive understanding of the specific properties of nanoparticles and their interaction potential with biological systems. This commentary justifies the requirement for comprehensive knowledge of the above-mentioned criteria and tests for the success of nanomedicine for chemotherapy delivery.

Determining Front-Line Therapeutic Strategy for Metastatic Clear Cell Renal Cell Carcinoma.

Simple SummaryKidney cancer occurs more commonly within the general population and has historically been associated with morbidity and early death. The most common form of kidney cancer is clear cell renal cell carcinoma. Thankfully, there now have multiple new therapies available for patients with metastatic disease that are improving the lives of patients. However, the number of new drugs and treatment types has created a degree of complexity in treatment planning. We review the most recent data in the metastatic disease space surrounding treatment for patients with newly diagnosed metastatic clear cell renal cell carcinoma. These treatments include surgery, radiation, and systemic therapies. Current systemic therapies include drugs that activate the immune system to target cancer cells and small-molecule drugs that target a cancer cell’s ability to grow and survive.The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development of biomarkers will certainly assist in this setting, and validation of predictive markers represents an unmet need. In their absence, we highlight features of disease and nuances to datasets from landmark prospective clinical trials to help inform treatment selection. There is growing evidence to support deferring upfront systemic therapy in some patients, with opportunities for active surveillance or metastasis-directed therapy. In others, upfront systemic therapy is warranted and necessitates thoughtful consideration of multiple clinicopathologic parameters to inform optimal patient-centered decision making.

Influence of ancestry in racial disparities of squamous cell lung cancer.

e20554 Background: Significant progress has been made in the screening, diagnosis, and treatment of squamous cell carcinomas of the lung (LUSC). Despite the advancements, African American populations continue to experience worse disease burden and poorer overall survival, even after controlling for patient and tumor characteristics. While the interplay of various social determinants of health is well known to contribute to racial disparities in cancers, the molecular basis of racial disparity is less understood. Given the diversity of the US population that comprise of genetically admixed groups, understanding the role of ancestry and its influence on biology of cancers that drive incidence and prognosis is paramount to reducing racial disparities. Therefore, in this study, we aimed to investigate the influence of African (AFR) ancestry in genetic mutations of LUSC. Methods: We utilized The Cancer Genome Ancestry Atlas (TCGAA) to obtain data on the genetic ancestry and ancestral composition of 504 LUSC patients. The dataset contained 459 self-reported whites, 32 blacks, and 11 Asians. The percentage of each patient’s ancestral composition (European, AFR, Asian, and Native American) was revealed via the LAMP technique. The dominant ancestry was defined as those with genetic composition of ≥50% from one of four ancestral backgrounds. Genetic alteration profiles and clinical data of patients were obtained from LUSC TCGA PanCancer Atlas through GDC data portal. Of those with AFR dominant ancestry, we analyzed the differences in the gene mutation frequency based upon the proportion of AFR ancestry. Results: Ancestry analysis uncovered 30 AFR ancestry dominant cases with a mean AFR composition of 78.4%. We found 14 subjects with > 80% AFR ancestry and 16 subjects with 50-80% AFR ancestry. Two patients from the > 80% were excluded from the mutational analyses due to absence of genetic profiles in the data portal. TP53 was the most frequently mutated gene with a rate of 91.7% and 87.5% in > 80% and 50-80% AFR groups, respectively. Evaluation of the classic genetic mutations that drive disease pathology in LUSC (EGFR, ALK, PIK3CA, NRAS, KRAS) revealed 25% of > 80% AFR ancestry subjects carried mutations in at least one of these genes compared to 6.3% in the 50-80% AFR ancestry subjects. Also, a trend towards worse overall survival (OS) was seen in those with greater proportion of AFR ancestry (median OS of 27.2 months in > 80% group vs 43.9 months in 50-80% group). Conclusions: Despite the limited sample size, our study highlights substantial heterogeneity in tumor biology even within those of AFR ancestry and that genetic ancestry may impact tumor and host biology that contribute to disparities. Moving forward, engagement of the African American community into clinical trials and genomic studies are needed to explore ancestral influence on tumorigenesis, and to facilitate discovery of new actionable targets to help eradicate racial disparities in lung cancer.

Current State of Neoadjuvant Radiotherapy for Rectal Cancer

Colorectal cancer is the third most commonly diagnosed cancer, with rectal cancer accounting for 30% of cases. The current standard of care curative treatment for locally advanced rectal cancer is (chemo)radiotherapy followed by surgery and adjuvant chemotherapy. Although neoadjuvant radiotherapy has reduced the risk of local recurrence to less than 10%, the risk of distant metastasis remained high at 30% affecting patient survival. In addition, there is a recognition that there is heterogeneity in tumor biology and treatment response with good responders potentially suitable for treatment de-escalation. Therefore, new treatment sequencing and regimens were investigated. Here, we reviewed the evidence for current neoadjuvant treatment options in patients with locally advanced rectal adenocarcinoma, and highlight the new challenges in this new treatment landscape.

Beyond the Guidelines: The Grey Zones of the Management of Gastric Cancer. Consensus Statements from the Gastric Cancer Italian Network (GAIN).

Simple SummaryManagement of gastric and gastroesophageal junction (GEJ) adenocarcinoma remains challenging, because of the heterogeneity in tumor biology within the upper gastrointestinal tract. This manuscript is the product of a formal consensus process conducted in three Delphi rounds and a consensus meeting by the GAIN (GAstric cancer Italian Network) group. The goal of this document is to present a synthesis of available evidence and, where this is lacking, to provide expert opinion directed at prevention, diagnosis, and proper management of gastric and GEJ adenocarcinoma, and in particular aspects of practical management not fully supported by guidelines.Background: Management of gastric and gastroesophageal junction (GEJ) adenocarcinoma remains challenging, because of the heterogeneity in tumor biology within the upper gastrointestinal tract. Daily clinical practice is full of grey areas regarding the complexity of diagnostic, staging, and therapeutic procedures. The aim of this paper is to provide a guide for clinicians facing challenging situations in routine practice, taking a multidisciplinary consensus approach based on available literature. Methods: The GAIN (GAstric cancer Italian Network) group was established with the aims of reviewing literature evidence, discussing key issues in prevention, diagnosis, and management of gastric and GEJ adenocarcinoma, and offering a summary of statements. A Delphi consensus method was used to obtain opinions from the expert panel of specialists. Results: Forty-nine clinical questions were identified in six areas of interest: role of multidisciplinary team; risk factors; diagnosis; management of early gastric cancer and multimodal approach to localized gastric cancer; treatment of elderly patients with locally advanced resectable disease; and treatment of locally advanced and metastatic cancer. Conclusions: The statements presented may guide clinicians in practical management of this disease.

The Genomic Complexity of Multiple Myeloma Precursor Disease Can be Predicted Using Copy Number Signatures on Targeted Sequencing and SNP Array Data

The Genomic Complexity of Multiple Myeloma Precursor Disease Can be Predicted Using Copy Number Signatures on Targeted Sequencing and SNP Array Data

Surgical treatment of non-functioning pancreatic neuroendocrine tumors: current controversies and challenges

Abstract There has been a rising trend in the incidence and prevalence of non-functioning pancreatic neuroendocrine tumors (NFPanNETs). While a significant number of the newly diagnosed NFPanNETs are asymptomatic, a majority of patients will present with liver metastasis (LM) at the time of diagnosis. Surgical resection remains the only curative treatment, especially for localized NFPanNETs. While a majority of small NFPanNETs are indolent, some are not. This heterogeneity in tumor biology presents the surgeon with the unique challenge of determining which patient will benefit from surgery, given the morbidity of pancreatic surgery. There has been a recent push for a more aggressive approach to the care of these patients, given the emergence of data supporting such measures. However, the risk of over or under treatment has generated immense debate amongst experts in the field. The heterogeneity of current practice guidelines and institutional practices around the world is a reflection of the disparate opinion on the management of NFPanNET. In this review, we set out to examine the evidence regarding some of the most controversial and challenging aspects of the surgical treatment of NFPanNET. We evaluate the following questions; should patients with small NFPanNETs ≤ 2 cm in size be resected; should patients with metastatic NFPanNETs undergo surgical debulking, and should there be resection of the primary tumor in the setting of non-resectable metastatic disease? Although there are currently no Level 1 data to answer these questions conclusively, we believe that the current literature supports a more aggressive approach to the management of NFPanNET.

Steering Efficacy of Nano Molybdenum Towards Cancer: Mechanism of Action.

Conventional cancer therapies possess a plethora of limitations which led to the awakening of nanotechnology and nanomedicine. However, technological success is widely dependent on complete understanding of the complexity and heterogeneity of tumor biology on one hand and nanobiointeractions associated with challenges of synthesis, translation, and commercialization on the other. The present study therefore deals with one such targeted approach aiming at synthesizing, characterizing, and understanding the efficacy of molybdenum oxide nanoparticles. The phase structure, morphology, and elemental composition of the synthesized nanoparticles were characterized using Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and scanning electron microscopy. The cytotoxicity studies revealed that the IC50 vales of molybdenum trioxide (MoO3) particles against skin cancer cells (melanoma and non-melanoma) were around 200–300 μg. The nanoparticles were found to induce mitochondrial-mediated apoptosis driven by the apoptotic genes such as BAX and Bcl2. Molybdenum being a cofactor for the majority of metabolic enzymes could have triggered the selective internalization of the nanoparticles which in turn could have modified the granularity of the cytoplasm and subsequently lead to mitochondrial-mediated apoptosis. Further, the anti-angiogenic property of MoO3 nanoparticles was corroborated using Chick chorioallantoic membrane (CAM) assay and aortic ring assay. Taken together , unraveling the role of MoO3 nanoparticles in cancer and angiogenesis opens up venues for nano biological intervention of selective cancer cell targeting with minimal damage to the normal cells using natural trace elements that are generally known to influence various metabolic enzymes.

Neoadjuvant Therapy for Breast Cancer: State of the Science and Future Directions

Systemic neoadjuvant chemotherapy has long been known to confer clinical benefits for breast cancer patients by downstaging inoperable disease or providing those with operable disease the opportunity for breast conservation, without compromising risk of recurrence. In recent years, its benefits have broadened as it has become a pivotal platform for clinical research, providing new prognostic and predictive insights into in vivo response to therapy and long-term outcomes. The use of neoadjuvant chemotherapy in the research setting has expanded our knowledge of heterogeneity in tumor biology and chemosensitivity and provided insights into the relationships between molecular signatures of tumors, pathologic complete response (pCR), and long-term outcomes. This has provided opportunities to specifically select patients who might benefit from novel therapies and test these in a more efficient manner. Despite these major advancements, however, the majority of patients do not attain a pathologic complete response with systemic neoadjuvant chemotherapy. This review describes the standard of care for systemic neoadjuvant therapy for breast cancer and discusses current management controversies and ongoing clinical trials designed to increase the proportion of patients who currently achieve a pCR.

Predictors of outcome in bladder cancer.

Tumor stage and grade have largely been responsible for directing treatment algorithms in bladder cancer. However, the considerable heterogeneity of tumor biology in bladder cancer is incompletely characterized by stage and grade alone, and recent efforts to improve predictive models in bladder cancer may significantly improve accuracy and calibration. This article addresses how current nomograms and risk tables may be best used to individualize bladder cancer management.

Patterns of Local Failure in Locally-Advanced Larynx and Hypopharynx Cancers

Intensity modulated radiation therapy (IMRT) with chemotherapy for locally advanced laryngeal and hypopharyngeal cancer provides a local control rate of 60-70%. IMRT allows for high conformity with steep dose gradients. If an area of tumor or subclinical disease is underdosed, local failure may occur. We retrospectively evaluated patients with laryngeal and hypopharyngeal cancers and investigated whether any dosimetric variations could predict for local failure. From 2003 to 2011, 58 patients with locally advanced laryngeal (74%) and hypopharyngeal (26%) squamous cell carcinomas treated with definitive IMRT with concurrent chemotherapy with at least 6 months follow-up were analyzed. IMRT was delivered with a simultaneous integrated boost technique. A median dose of 70 Gy (range, 64.6-74.4) was delivered to regions of gross disease and 59.9 Gy to the at-risk nodal regions; both given in 35 fractions. The GTV size and the following dosimetric parameters of the PTV were reviewed: Dmax, Dmean, D99, V70 and V66. PET/CT with evidence of local failure was fused to planning CT to evaluate the relationship between site of local recurrence and treatment plan. These fusions were analyzed to determine if the recurrence fell within the PTV and received at least 95% of the prescription dose. Median follow-up was 27 months (range, 5-100 months). Stage distribution was: T1 - 10%, T2 - 34%, T3 - 36%, T4 - 19%; stage II - 10%, III - 25%, IVA - 54%, and IVB - 8%. There were 17 local failures. The one and two year actuarial local control rates were 79% and 70%, respectively. The median time to local failure was 6.2 months (range, 2.7-22.0 months). The median values of the analyzed PTV parameters were: Dmax 77.9 Gy (range, 68.9-86.2 Gy), D99 65.2 Gy (range, 49.1-70.1 Gy), Dmean 72.4 Gy (range, 66.4-75.2 Gy), V70 87.8% (range, 0-99), V66 98.4% (range, 75.7-100). The median GTV was 46.0 cc (range, 6.57-519 cc). T4 disease correlated with local failure (73% vs 27% for non-T4 disease, p < 0.01). There was no correlation with GTV size or treatment duration with rates of local failure. Additionally, none of the evaluated dose parameters were associated with local control rates. Nine (53%) of the local failures represented incomplete responses to radiation; the other 8 (47%) recurred after a complete response. Sixteen of the 17 (94%) local failures were within the PTV and 95% isodose line. One patient failed 2 cm away from the PTV 8 months after treatment. Local control remains a concern in the management of locally advanced laryngeal cancer. In our series, local failure is not associated with lower dose to target volume and 16 of the 17 tumors failed in tissue that had received a high radiation dose. This suggests that heterogeneity in tumor biology may be responsible for local failure. Identifying biomarkers that correlate with radio resistance may allow for alternative treatment considerations, such as novel molecular targeted agents or upfront surgery.

Abstract 1818: Gene expression profiling to understand stages in breast cancer development and progression: importance of tissue sampling and context .

Abstract Background: During the past decade, gene expression profiling has been widely employed to understand the heterogeneity of tumor biology. Novel biomarkers and signatures discovered using these techniques have impacted tumor diagnosis and prognosis, and have led to important insights into etiology. However, application of mRNA profiling to define mechanisms mediating breast cancer risk factor exposure remains underexplored. Identifying mediating pathways of breast carcinogenesis by tumor tissue profiling may be problematic because genomic instability may obscure causal changes. Methods: To evaluate how etiologically relevant signatures are expressed during different stages of carcinogenesis, we analyzed gene expression data from three types of whole tissue samples: benign tissues from non-diseased breasts (“normal”), benign tissues adjacent to cancer (“cancer-associated”), and tumors. We assessed three published signatures (Age, Obesity, and Parity, originally defined in “normal” breast tissues from healthy women) in 149 tumor tissues and paired cancer-adjacent benign tissues from the Polish Women's Breast Cancer Study. Associations of chronological age, body mass index and parity with their related mRNA signatures were evaluated. Results: The association between Obesity signature and actual obesity status showed a marked gradient from normal breast tissues (obese vs. non-obese: OR=5.78, p=0.0009) to cancer-adjacent and tumor tissues (cancer-adjacent: OR=1.85, p=0.09; tumor: OR=0.80, p=0.54). A similar pattern was also observed for Age signature (normal: OR [&amp;lt;40 y vs. ≥ 40y] =5.03, p&amp;lt;0.0001; cancer-adjacent: OR [&amp;lt;45 y vs. ≥ 45y] =6.97, p=0.005; tumor: OR=0.58 p=0.35) and Parity signature (parous vs. nulliparous, normal: OR =3.95, p=0.0002; cancer-adjacent: OR=1.38, p=0.44; tumor: OR=1.20, p=0.65). Simulation studies further demonstrated that the association strength was influenced by the proportion of risk factor-associated genes that were dysregulated during carcinogenesis. Differences in cellular composition between samples may also affect association strength. Conclusions: These results suggest that associations between risk factors and gene signatures are strongest in benign tissues from non-diseased breasts and may be weakened by the responses of cancer-adjacent issues to cancer progression, and by the effects of genomic instability in tumors. While tumor tissue is readily available in many epidemiologic studies, use of this tissue for studying etiologically relevant pathways may have important limitations. Identification of etiologically relevant pathways may rely on studies of well-annotated tissues from women without cancer. Citation Format: Xuezheng Sun, Alexandre Lockhart, Gretchen L. Gierach, Mark Sherman, Jonine D. Figueroa, Sallie S. Schneider, D. Joseph Jerry, Melissa A. Troester. Gene expression profiling to understand stages in breast cancer development and progression: importance of tissue sampling and context . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1818. doi:10.1158/1538-7445.AM2013-1818 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

BRCAness: Finding the Achilles Heel in Ovarian Cancer

Ovarian cancer is the leading cause of death among gynecological cancers. It exhibits great heterogeneity in tumor biology and treatment response. Germline mutations of DNA repair genes BRCA1/2 are the fundamental defects in hereditary ovarian cancer that expresses a distinct phenotype of high response rates to platinum agents, improved disease-free intervals and survival rates, and high-grade serous histology. The term "BRCAness" describes the phenotypic traits that some sporadic ovarian tumors share with tumors in BRCA1/2 germline mutation carriers and reflects similar causative molecular abnormalities. BRCA pathway studies and molecular profiling reveal BRCA-related defects in almost half of the cases of ovarian cancer. BRCA-like tumors are particularly sensitive to DNA-damaging agents (e.g., platinum agents) because of inadequate BRCA-mediated DNA repair mechanisms, such as nucleotide-excision repair and homologous recombination (HR). Additional inhibition of other DNA repair pathways leads to synthetic lethality in HR-deficient cells; this has been employed in the treatment of BRCA-like ovarian tumors with poly(ADP-ribose) polymerase inhibitors with promising results. This article presents a comprehensive review of the relevant literature on the role of BRCAness in ovarian cancer with respect to BRCA function, methods of BRCA epigenetic defect detection and molecular profiling, and the implications of BRCA dysfunction in the treatment of ovarian cancer.

Race and Subset Analyses in Clinical Trials: Time to Get Serious About Data Integration

Colorectal cancer mortality rates have decreased in the last two decades primarily because of improved population screening rates and enhanced multimodality treatment of the disease (1). Because the decline in mortality rates among African American patients has not been as substantial as in white patients of European descent, the disparity in stage-specific survival between African Americans and whites continues to widen (2,3). Multiple factors contribute to the lower survival of African American patients, including reduced access to quality primary care that can lead to less preventative care, higher rates of comorbidities, diagnosis at later stages of disease, and lower utilization of potentially curative treatment after diagnosis (4–7). Unfortunately, there has been a paucity of integrated data at both the individual and population levels to develop effective policies to close the gap. In this issue of the Journal, Yothers et al. (8) sought to determine whether black (African American or of African ancestry) colon cancer patients with stage II and III disease treated in an equivalent manner within the setting of clinical trials achieved similar cancer-specific and overall outcomes compared with white patients. The authors examined the overall survival, recurrencefree survival, and recurrence-free interval of 13 393 whites and 1218 blacks from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) collaborative group database. The strength of this study was the uniform collection of individual patient level data from participants in 12 adjuvant phase III clinical trials in North America from 1977 to 2002. The results of the study showed that under standardized treatment conditions, black patients still had statistically significant worse overall and recurrence-free survival compared with white patients, whereas both patient groups had a similar recurrence-free interval. Based upon these findings, the authors conclude that the worse survival of black patients is likely because of factors unrelated to response to adjuvant treatment, such as racial differences in comorbidities, general life expectancy, or potentially in care for recurrent disease. It is worth noting that despite the addition of a more contemporary cohort of patients, the results of this study are almost identical to those published in this Journal by Dignam et al. (9) more than a decade ago, which included only the first five National Surgical Adjuvant Breast and Bowel Project (NSABP) colon cancer trials (C-01 through C-05). Moreover, data within this study precede the adoption of biologic therapies for the treatment of advanced colorectal cancer and include outcome data from 5-fluorouracil (FU)-based therapies, which were broadly applied to patients without consideration of the molecular mechanisms driving disease progression. We now understand that colorectal cancers are of a heterogeneous nature (10–12) and should be treated as such. Therefore, studying the poorer overall and recurrence-free survival of African Americans compared with whites among a uniformly treated population without reference to the underlying heterogeneity in tumor biology limits interpretation of the study findings. Nevertheless, it is useful to examine what additive information is gleaned from each of the endpoints in this article (8). This study demonstrates a non-statistically significant 8% increase in the haz ard of recurrence for blacks compared with whites (hazard ratio = 1.08, 95% confidence interval = 0.97 to 1.19, P = .15) (8). The authors conclude that this supports either no difference in response to therapy or at best a very small difference. This conclusion has some caveats. Given the higher competing causes of death for black patients before potential recurrence (as evidenced by the poorer recurrence-free survival), recurrences that may have manifested will never occur, which biases the results toward the null hypothesis. More importantly, despite a very large sample size, the study still only included 1218 black patients, and of these, a little less than one-third had recurrence events. Given the heterogeneity in both tumor biology of colon cancer [eg, microsatellite instability

Talactoferrin alfa may prolong progression-free survival in advanced renal carcinoma patients

4600 Background: Talactoferrin alfa (formerly known as recombinant human lactoferrin, rhLF) is a novel immunomodulatory 80 kD protein with demonstrated oral anti-tumor properties in animal models, and promising early results in patients with advanced renal cell carcinoma (RCC) in Phase 1/2 trials. Methods: An open label Phase 2 study of Talactoferrin Oral Solution at 1.5 g talactoferrin alfa b.i.d. given up to a maximum of 4 cycles of 12 weeks on, 2 weeks off was conducted at 6 sites. Eligibility included predominantly clear cell histology, failure of at least one prior systemic therapy, tumor progression within the prior 9 months, a performance status of &lt;2 (ECOG) and adequate organ function. The primary endpoints were the incidence of 14-week progression-free survival (PFS) and overall tumor response (by RECIST). The statistical plan specified an objective of 12.5% response rate or a progression-free survival rate of ≥40% at 14 weeks. Secondary endpoints included median PFS and median overall survival (OS). Results: Forty-four patients were enrolled. Eighteen patients (41%) were considered low risk and twenty-six (59%) considered intermediate risk based on the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria. There were no talactoferrin-related Grade 3 or 4 adverse events or laboratory abnormalities. The most common related grade 1 or 2 adverse events were gastrointestinal symptoms. There was one unconfirmed tumor response and the 14-week PFS was 55%. The median PFS was 21 weeks (46 weeks and 9.4 weeks in the patients with low and intermediate risk prognostic factors, respectively). The median OS has not yet been reached. Conclusions: Talactoferrin alfa is well tolerated. The 14-week PFS met the pre-specified criteria for success (&gt;40%). Due to the heterogeneity of tumor biology of RCC, any further evaluation of talactoferrin in this population should be in a larger randomized trial. [Table: see text]