We propose a working hypothesis that integrates data from the CALGB/SWOG 80405 and FIRE-3 studies to explain apparent discrepancies in their results. Both trials assessed the combination of either ...cetuximab or bevacizumab with a different chemotherapy backbone: irinotecan in all patients in the FIRE-3 study, or oxaliplatin in 75% of the patients in the CALGB/SWOG 80405 study. The hypothesis is divided into three parts. Firstly, in addition to the biology or microenvironment of the tumour and the selection of the biologically targeted agents common to both trials, chemotherapy itself is an important variable that determines treatment efficacy because of a complex interplay between the biological therapy, the chemotherapy, and the microenvironment. Secondly, the tumour microenvironment, as defined by the Consensus Molecular Subtypes (CMS) classification, determines the interaction of chemotherapeutic agents with biologically targeted agents such as bevacizumab and cetuximab. Whereas irinotecan synergises with cetuximab across all CMS subtypes, oxaliplatin might have variable effects, synergising with cetuximab in fibroblast-poor microenvironments, such as CMS2 and CMS3, but activating fibroblast-rich microenvironments, such as CMS1 and CMS4, to release cytokines that might antagonise some of the cetuximab effects. Thirdly, the previous assumptions integrate into a final concept, which is that overall survival is determined not only by the biological therapy or the first-line treatment, but specifically by the sequence of first-line and second-line regimens, and the degree of synergism between them. In a clinical setting, the optimal first-line combination of biological therapy and chemotherapy predetermines the crossover to a specific second-line treatment, which affects the overall survival of a patient with a specific tumour subtype. Our working hypothesis suggests that the CALGB/SWOG 80405 and FIRE-3 studies are complementary rather than discrepant, and it provides an explanation for their opposing interpretations. In conclusion, proper interpretation of the CALGB/SWOG 80405 and FIRE-3 results requires an in-depth examination of the complex interplay, not only between the targeted biological agents and chemotherapeutic drugs, but also between therapies and the tumour biology and microenvironment, for each line of treatment.
Cetuximab and panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), and both are widely used in combination with chemotherapy or as ...monotherapy to treat patients with
RAS
wild-type metastatic colorectal cancer. Although often considered interchangeable, the two antibodies have different molecular structures and can behave differently in clinically relevant ways. More specifically, as an immunoglobulin (Ig) G1 isotype mAb, cetuximab can elicit immune functions such as antibody-dependent cell-mediated cytotoxicity involving natural killer cells, T-cell recruitment to the tumor, and T-cell priming via dendritic cell maturation. Panitumumab, an IgG2 isotype mAb, does not possess these immune functions. Furthermore, the two antibodies have different binding sites on the EGFR, as evidenced by mutations on the extracellular domain that can confer resistance to one of the two therapeutics or to both. We consider a comparison of the properties of these two antibodies to represent a gap in the literature. We therefore compiled a detailed, evidence-based educational review of the known molecular, clinical, and functional differences between the two antibodies and concluded that they are distinct therapeutic agents that should be considered individually during treatment planning. Available data for one agent can only partly be extrapolated to the other. Looking to the future, the known immune activity of cetuximab may provide a rationale for this antibody as a combination partner with investigational chemotherapy plus immunotherapy regimens for colorectal cancer.
Background
Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a ...reported relative risk of ∼5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients.
Materials and Methods
We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records.
Results
Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36–75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum‐based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression‐free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval CI, 6.73–108.15) and with stages III/IV was 25 months (95% CI, 15.23–40.57).
Conclusion
BRCA‐associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA‐associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials.
Implications for Practice
BRCA‐associated CCA is uncommon but a very important subtype of hepatic malignancies, due to its rising prevalence. Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes, especially due to previously reported success of such therapies in other BRCA‐associated malignancies. Thus this study, first of its kind, provides a basis for future multi‐centered analyses in larger cohorts, as well as clinical trials. Additionally, this study emphasizes the importance of both germline and somatic genotyping for all CCA patients.
摘要
背景. 胆道恶性肿瘤, 尤其是胆管癌（CCA）是一类预后不良的罕见肿瘤。BRCA2突变携带者罹患CCA的风险增加, 乳腺癌联合协作组报告的相对风险约为5。除上述风险以外, 这对于携带体细胞和/或胚系（GL）BRCA突变的患者而言还具有潜在治疗意义。因此, 确定CCA患者中GL/体细胞BRCA1/2变异体的临床特征至关重要。
材料和方法. 我们针对2000年1月至2013年12月期间诊断的携带GL或体细胞BRCA1/2基因变异体（通过GL突变检测方法和/或新一代肿瘤测序技术检测）的CCA患者进行了一项多中心回顾性分析。从参与机构的临床数据库中检索病例。研究数据包括人口统计学、临床病史、手术方式以及全身化疗或放疗, 以上信息摘自患者记录。
结果. 共计检索到18例病例：5例携带GL BRCA1/2突变（4例BRCA2；1例BRCA1）, 13例携带体细胞变异（7例BRCA1；6例BRCA2）。诊断时的平均年龄为60岁, SD±10岁（范围：36‐75岁）, 男性和女性的患病率分别为61.2%和38.8%。诊断时的疾病分期包括I期（n=4）、II期（n=3）、III期（n=3）和IV期（n=8）。6例患者为肝外CCA, 其余为肝内CCA。13例患者接受以铂类药物为基础的治疗, 4例患者接受多聚ADP核糖聚合酶抑制剂（PARPi）治疗, 其中1例患者获得了持久性疾病缓解, 无进展生存期为42.6个月。在本研究中, 自诊断时起, I/II期患者的中位总生存期为40.3个月95%置信区间（CI）：6.73‐108.15, III/IV期患者的中位总生存期为25个月（95% CI：15.23‐40.57）。
结论. BRCA相关性CCA并不常见。本项多中心回顾性研究针对一个BRCA相关性CCA队列进行了全面的临床分析, 在日后开发和设计扩展分析和临床试验时可以此作为基准。
It is unknown if and to what extent the clinical course and therapeutic response of BRCA‐associated cholangiocarcinomas are distinct from non‐BRCA carriers. To gain insight, this multicenter retrospective study on BRCA‐associated cases was initiated and is reported here.
Previous studies have shown that elevated preoperative carcinoembryonic antigen (CEA) levels are associated with worse prognosis in patients with colon cancer. These studies compared the prognosis of ...patients with elevated versus normal CEA levels. We sought to assess the prognostic role of increasing levels of CEA in stage I and II patients who did not receive adjuvant chemotherapy.
Using the National Cancer Database (2004–2014), we identified 45,449 individuals with stage I and II colon cancer who did not receive adjuvant chemotherapy and had preoperative CEA levels available. We estimated the optimal cut-point of CEA levels to predict survival using the Youden Index. Cox proportional hazards were used to compare individuals with CEA levels above and below the defined cut-point. In a secondary analysis, we examined the prognostic value of stage, age and tumour location.
The optimal preoperative CEA cut-point to predict survival was 2.35 ng/mL. The adjusted HR for overall survival among individuals with preoperative CEA levels at or above compared with below 2.35 ng/mL was 1.56 (95% CI, 1.49–1.64). Individuals with CEA levels below 2.35 ng/mL had higher 3-year survival rates compared with those with CEA levels above 2.35 ng/mL (79.7% vs 64.5%, respectively).
Preoperative CEA levels at or above 2.35 ng/mL, found within the normal range, may be used to identify stage I and II colon cancer patients harbouring worse prognosis.
•Elevated preoperative carcinoembryonic antigen (CEA) levels are associated with worse prognosis in patients with colon cancer.•In our study, CEA levels above 2.35 ng/mL, found within the normal range, confer worse prognosis in stage I/II colon cancer.•This cut-point may trigger more intensive surveillance, such as more frequent colonoscopies or routine imaging.
Background
Synchronous peritoneal and liver metastasis in colorectal cancer is a relative contraindication for curative surgery. We aimed to evaluate the safety and oncological outcomes of combined ...treatment of peritoneal and liver metastasis.
Methods
We conducted a retrospective analysis of metastatic colorectal cancer patients from two prospective databases: peritoneal surface malignancy (
n
= 536) and hepatobiliary (
n
= 286). We compared 60 patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and hepatectomy; 80 patients treated with cytoreduction and HIPEC only; and 63 patients treated with hepatectomy alone.
Results
No differences in demographics were observed between the groups. Median hospital and intensive care unit (ICU) stay was shorter in group C (7 and 1 days, respectively) versus groups A and B (13 and 1 days, and 12 and 1 days, respectively;
p
< 0.001). Postoperative complications were not significantly different. Median follow-up was 18.6, 23.1, and 30.6 months for groups A, B, and C, respectively. Estimated 5-year overall survival (OS) was 48.8% (group A), 55.4% (group B), and 60.2% (group C)
p
= 0.043 for group A vs. group C, and estimated 5-year disease-free survival (DFS) was 14.2% (group A), 23.0% (group B), and 18.6% (group C). Five-year OS was superior in group C compared with group A (
p
= 0.043), and DFS was superior in group C compared with groups A and B (
p
= 0.043 and 0.03, respectively). The peritoneum was the site of first recurrence in groups A and B (23.3% and 32.5%, respectively), and the liver was the site of first recurrence in group C (44.4%).
Conclusions
We report favorable perioperative and oncological outcomes in combined cytoreduction/HIPEC and hepatectomy for patients with peritoneal and liver metastasis. Surgical intervention after multidisciplinary discussion should be considered in patients with both peritoneal and hepatic lesions when complete cytoreduction is feasible.
Ovarian cancer (OvCA) remains one of the most devastating malignancies, but treatment options are still limited. We report that amphiregulin (AREG) can serve as an effective and safe pharmacological ...target in a syngeneic murine model. AREG is highly abundant in abdominal fluids of patients with advanced OvCa. In immunocompetent animals, depletion or overexpression of AREG respectively prolonged or shortened animal survival. A new antibody we generated in AREG-knockout mice recognized murine AREG and reproducibly prolonged animal survival in the syngeneic model. The underlying mechanism likely involves binding of wildtype p53 to AREG's promoter and autocrine activation of the epidermal growth factor receptor (EGFR), a step blocked by the antibody. Accordingly, depletion of p53 downregulated AREG secretion and conferred tolerance, whereas blocking an adaptive process involving CXCL1, which transactivates EGFR, might increase therapeutic efficacy. Consistent with these observations, analysis of OvCa patients revealed that high AREG correlates with poor prognosis of patients expressing wildtype TP53. In conclusion, clinical tests of the novel antibody are warranted; high AREG, normal TP53, and reduced CXCL1 activity might identify patients with OvCa who may derive therapeutic benefit.
Background
Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) for colorectal cancer peritoneal metastases (CRPM) is associated with improved survival in patients with ...historically dismal prognosis. Nonetheless, peritoneal recurrences remain common and represent a difficult challenge in these patients' management. Repeat CRS/HIPEC is associated with even greater morbidity and its survival benefit has not yet been clearly demonstrated.
Methods
We retrospectively reviewed our prospectively maintained database and aimed to assess the safety and oncological efficacy of repeat CRS/HIPEC.
Results
Two hundred thirty-two patients underwent an initial CRS/HIPEC, whereas 30 subsequently had repeat CRS/HIPEC for CRPM. Groups were similar in demographics, comorbidities, and peritoneal cancer index (PCI). No significant difference in morbidity, hospital stay, or reoperation rate was noted between initial and repeat procedures. Patients who underwent repeat CRS/HIPEC had a median overall survival of 68 months versus 51 months in patients who did not undergo repeat procedure for their peritoneal recurrence (
p
= 0.03). Disease-free survival (DFS) in patients after repeat and after initial procedure were similar with median of 9.6 versus 12 months, respectively (
p
= 0.083). Univariate analysis demonstrated that PCI, DFS, and repeat procedure displayed significant factors on outcomes in patients with peritoneal recurrences, whereas PCI > 16 and DFS remained independent predictors on multivariable analysis.
Conclusions
Our analysis, which represents the largest series to date of repeat CRS/HIPEC for CRPM, indicates that this approach as a part of multimodal therapy is both safe and efficacious in appropriately selected patients.
The role of TNF receptors (TNF-Rs) is not limited to signal transduction but includes extracellular regulatory functions affecting systemic TNF bioavailability. This review summarizes the regulation ...of TNF-R shedding and its kinetics, the complex interaction between the soluble receptors and their ligand
in vitro and
in vivo, and the potential diagnostic, prognostic and therapeutic value of the soluble receptors in malignant, inflammatory, infectious and autoimmune disorders.
Several studies suggested that curcumin inhibits growth of malignant cells via inhibition of cyclooxygenase-2 (COX-2) activity. Other studies indicated that epidermal growth factor receptor (EGFR) is ...also inhibited by curcumin in vitro and in vivo. Moreover, recent investigations revealed an intracellular cross-talk between EGFR signaling and the COX-2 pathway. Our aim was to evaluate whether the curcumin inhibitory effect on the survival of cancer cells is associated with simultaneous down-regulation of COX-2 and EGFR and inhibition of Erk1/2 (extra-cellular signal regulated kinase) signaling pathway.
Lung and pancreas adenocarcinoma cell lines co-expressing COX-2 and EGFR (PC-14 and p34, respectively) and those expressing EGFR but deficient in COX-2 (H1299 and Panc-1, respectively) were exposed for 72 h to curcumin (0-50 microM). Cell viability was assessed by the XTT assay. Apoptosis was determined by FACS analysis. COX-2, EGFR, ErbB-2 and p-Erk1/2 expressions were measured by Western blot analysis.
Curcumin's inhibitory effect on survival and apoptosis of lung and pancreatic adenocarcinoma cell lines was significantly higher in the COX-2-expressing cells than in the COX-2-deficient cells. In the p34 and PC-14 cells, curcumin decreased COX-2, EGFR and p-Erk1/2 expressions in a dose-dependent manner. However, in the Panc-1 and H1299 cell lines, which did not express COX-2, curcumin did not affect EGFR levels.
Curcumin co-inhibited COX-2 and EGFR expression and decreased Erk1/2 activity. This inhibition was associated with decreased survival and enhanced induction of apoptosis in lung and pancreatic adenocarcinoma cells.
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