Abstract Background: Two groups of agents targeting either the vascular endothelial growth factor (VEGF) receptor or the epidermal growth factor receptor (EGFR) have been added to the therapeutic ...arsenal against metastatic colorectal cancer (mCRC). Currently available agents in these groups are the anti-VEGF antibody bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab. Objectives: This article reviews the results of prospective randomized clinical trials of anti-VEGF and anti-EGFR antibodies in mCRC, either as monotherapy, combined with chemotherapy, or combined with each other. Also reviewed are retrospective subset analyses of the effect of a KRAS mutation on the response to anti-EGFR antibodies. Methods: MEDLINE (2004–2009) was searched for randomized Phase II-III clinical trials of monoclonal antibodies in mCRC published in English. The search terms were colorectal neoplasms, bevacizumab, cetuximab, panitumumab , and KRAS mutation , alone or in combination. Information on the effect of KRAS mutation status on the response to anti-EGFR antibodies was drawn from retrospective subset analyses within the selected trials. Results: The literature search identified 5 trials of bevacizumab in mCRC. Of these trials, 3 found a significant benefit on the primary end point (progressionfree survival PFS or overall survival OS) when bevacizumab was added to chemotherapy, either as first-line (2 trials) or second-line (1 trial) treatment. The literature search identified 5 trials of cetuximab and 1 trial of panitumumab in mCRC. Of these trials, 4 found a significant benefit on the primary end point (response rate, PFS, or OS) with cetuximab or panitumumab as monotherapy or added to chemotherapy, either as first-line (1 trial) or later-line (3 trials) treatment. In all trials, the benefit of anti-EGFR therapy was limited to patients who had KRAS wild-type tumors. Of 3 identified trials of combined anti-EGFR and anti-VEGF therapy, 2 found that the combination of an anti-EGFR antibody and the anti-VEGF antibody bevacizumab had a significant negative effect on the primary end point (PFS) compared with no added anti-EGFR antibody. Conclusions: In the studies reviewed, the anti-VEGF antibody bevacizumab added to chemotherapy and the anti-EGFR antibodies cetuximab and panitumumab as monotherapy or added to chemotherapy were associated with consistent efficacy in the treatment of mCRC, although the absolute benefit differed among trials. The efficacy of anti-EGFR antibodies was limited to patients with KRAS wild-type tumors. Given the lack of benefit when anti-VEGF and anti-EGFR antibodies were combined, such regimens should not be used in clinical practice.
Summary Background The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was ...designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. Methods In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00442637. Findings Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36–57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56–0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 23% patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. Interpretation Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. Funding Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.
Capecitabine, oxaliplatin, and bevacizumab are standard treatment for metastatic colorectal cancer. This trial tested whether adding cetuximab to this combination is beneficial. The addition of ...cetuximab resulted not only in shorter progression-free survival than standard treatment but also in a reduced quality of life.
This trial tested whether adding cetuximab to standard treatment for metastatic colorectal cancer is beneficial. The addition of cetuximab resulted not only in shorter progression-free survival than standard treatment but also in a reduced quality of life.
Fluoropyrimidines (e.g., fluorouracil and capecitabine), irinotecan, and oxaliplatin are the standard cytotoxic drugs used in treating metastatic colorectal cancer.
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The combination of capecitabine and oxaliplatin is similar to the combination of fluorouracil and capecitabine in efficacy and safety.
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Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF),
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combined with fluoropyrimidine-based chemotherapy is now the standard first-line treatment for metastatic colorectal cancer. Cetuximab, a chimeric IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR), has efficacy as monotherapy and in combination with irinotecan in irinotecan-resistant patients.
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We prospectively evaluated the addition of cetuximab to capecitabine, . . .
Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by ...several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi‐induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi‐induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi‐induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune‐mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi‐induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm.
Purpose
The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease ...course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC).
Methods
Patients diagnosed with ABC in seven hospitals in 2007–2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates.
Results
Overall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51–0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69–15.20).
Conclusion
The HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.
Purpose
Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the ...real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype.
Patients and methods
We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008–2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan–Meier method and differences between periods (2008–2012 versus 2013–2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest.
Results
The median OS in 2008–2012 versus 2013–2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66–1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72–1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38–0.92). Any HER2-targeted therapy was used in 79% of patients in 2008–2012 and in 84% in 2013–2017. The use of pertuzumab and T-DM1 in 2013–2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013–2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1.
Conclusion
The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.
Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumour biology. Here we describe the genomic landscape of tumour samples of a homogeneous well-annotated ...series of patients with metastatic CRC (mCRC) of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal subregions are associated with progression-free survival (PFS; uncorrected single-test P-values <0.005). These subregions are filtered for effect on messenger RNA expression, using an independent data set from The Cancer Genome Atlas which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of mCRC reveals a number of DNA copy number aberrations associated with response to drug therapy.
Breast cancer treatment depends on human epidermal growth factor receptor-2 (HER2) status, which is often determined using dual probe fluorescence in situ hybridisation (FISH). Hereby, also loss and ...gain of the centromere of chromosome 17 (CEP17) can be observed (HER2 is located on chromosome 17). CEP17 gain can lead to difficulty in interpretation of HER2 status, since this might represent true polysomy. With this study we investigated whether isolated polysomy is present and how this effects HER2 status in six breast cancer cell lines and 97 breast cancer cases, using HER2 FISH and immunohistochemistry, DNA ploidy assessment and multiplex ligation dependent probe amplification. We observed no isolated polysomy of chromosome 17 in any cell line. However, FISH analysis did show CEP17 gain in five of six cell lines, which reflected gains of the whole chromosome in metaphase spreads and aneuploidy with gain of multiple chromosomes in all these cases. In patients' samples, gain of CEP17 indeed correlated with aneuploidy of the tumour (91.1%; p < 0.001). Our results indicate that CEP17 gain is not due to isolated polysomy, but rather due to widespread aneuploidy with gain of multiple chromosomes. As aneuploidy is associated with poor clinical outcome, irrespective of tumour grade, this could improve future therapeutic decision making.
Background
Clinical practice guidelines recommend to inform female cancer patients about their infertility risks due to cancer treatment. Unfortunately, it seems that guideline adherence is ...suboptimal. In order to improve quality of integrated female oncofertility care, a systematic assessment of current practice is necessary.
Methods
A multicenter cross‐sectional survey study in which a set of systematically developed quality indicators was processed, was conducted among female cancer patients (diagnosed in 2016/2017). These indicators represented all domains in oncofertility care; risk communication, referral, counseling, and decision‐making. Indicator scores were calculated, and determinants were assessed by multilevel multivariate analyses.
Results
One hundred twenty‐one out of 344 female cancer patients participated. Eight out of 11 indicators scored below 90% adherence. Of all patients, 72.7% was informed about their infertility, 51.2% was offered a referral, with 18.8% all aspects were discussed in counseling, and 35.5% received written and/or digital information. Patient's age, strength of wish to conceive, time before cancer treatment, and type of healthcare provider significantly influenced the scores of three indicators.
Conclusions
Current quality of female oncofertility care is far from optimal. Therefore, improvement is needed. To achieve this, improvement strategies that are tailored to the identified determinants and to guideline‐specific barriers should be developed.
This study demonstrated that the quality of integrated female oncofertility care measured with a set of systematically developed quality indicators is far from optimal and needs improvement.
KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required ...to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab.
Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR.
Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model.
Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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