Automated image analysis of cells and tissues has been an active research field in medical informatics for decades but has recently attracted increased attention due to developments in computer and ...microscopy hardware and the awareness that scientific and diagnostic pathology require novel approaches to perform objective quantitative analyses of cellular and tissue specimens. Model-based approaches use a priori information on cell shape features to obtain the segmentation, which may introduce a bias favouring the detection of cell nuclei only with certain properties. In this study we present a novel contour-based "minimum-model" cell detection and segmentation approach that uses minimal a priori information and detects contours independent of their shape. This approach avoids a segmentation bias with respect to shape features and allows for an accurate segmentation (precision = 0.908; recall = 0.859; validation based on ∼8000 manually-labeled cells) of a broad spectrum of normal and disease-related morphological features without the requirement of prior training.
We investigated disease-free survival (DFS) and overall survival (OS) after response-guided neoadjuvant chemotherapy in patients with early breast cancer.
We treated 2,072 patients with two cycles of ...docetaxel, doxorubicin, and cyclophosphamide (TAC) and randomly assigned early responders to four (n = 704) or six (n = 686) additional TAC cycles, and early nonresponders to four cycles of TAC (n = 321) or vinorelbine and capecitabine (NX; n = 301) before surgery.
DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio HR, 0.78; 95% CI, 0.62 to 0.97; P = .026), and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P = .001). Exploratory analysis showed that DFS after response-guided chemotherapy (TAC × 8 or TAC-NX) was significantly longer (HR, 0.71; 95% CI, 0.60 to 0.85; P < .003), as was OS (HR, 0.79; 95% CI, 0.63 to 0.99; P = .048), than on conventional chemotherapy (TAC × 6). DFS was longer after response-guided chemotherapy in all hormone receptor-positive tumors (luminal A HR = 0.55, luminal B human epidermal growth factor receptor 2 (HER2) negative HR = 0.40, and luminal B HER2 positive HR = 0.56), but not in hormone receptor-negative tumors (HER2 positive nonluminal HR = 1.01 and triple negative HR = 0.87). Pathologic complete response did not predict these survival effects. pCR predicted an improved DFS in triple-negative (HR = 6.67), HER2-positive (nonluminal; HR 5.24), or luminal B (HER2-negative) tumors (HR = 3.74).
This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer.
PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate ...in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate ...end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.
Summary Background In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial ...assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment. Method In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m2 (after study amendment, 125 mg/m2 ) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m2 plus intravenous cyclophosphamide 600 mg/m2 on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response 33% minus a 10% non-inferiority margin 3·3%; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov , number NCT01583426. Findings Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m2 due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 38%, 95% CI 35–42 patients) than in the solvent-based paclitaxel group (174 29%, 25–33 patients; OR 1·53, 95% CI 1·20–1·95; unadjusted p=0·00065). The incidence of grade 3–4 anaemia (13 2% of 605 patients in the nab-paclitaxel group vs four 1% of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3–4 (63 10% patients receiving any nab-paclitaxel dose; 31 8% of patients starting with 125 mg/m2 and 32 15% of patients starting with 150 mg/m2 ; vs 16 3% in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure). Interpretation Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer. Funding Celgene, Roche.
Background
Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with ...the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF
165
b in breast cancer.
Conclusions and perspectives
Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/
165
b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies.
Breast Cancer (BC) can be classified using pathologic features, such as grade and tumor size. It can be categorized based on the gene expression profile, which identifies the distinct molecular ...subtype. More recently, stromal tissue has been recognized as an important modulator of tumor cell growth, pathogenesis, and progression. Immune cells could drive important clinical characteristics that affect BC outcomes. Subgroups of patients who have tumor-infiltrating lymphocytes in the stroma may have better response to chemotherapy and favorable long-term prognosis. Accumulating evidence shows that the immune system plays a crucial role in the outcomes of some BC subgroups, especially more aggressive, proliferative ones such as triple-negative and HER2-positive BC. This review article will present data on the role of lymphocyte infiltration in BC prognosis and response to therapy. This review will also introduce the reader to the challenges of applying this promising prognostic and predictive biomarker in clinical practice.
The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to ...substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.
The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed ...patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies.
Apart from genetic alterations, development and progression of colorectal cancer has been linked to influences from nutritional intake, hyperalimentation, and cellular metabolic changes that may be ...the basis for new diagnostic and therapeutic approaches. However, in contrast to genomics and proteomics, comprehensive metabolomic investigations of alterations in malignant tumors have rarely been conducted.
In this study we investigated a set of paired samples of normal colon tissue and colorectal cancer tissue with gas-chromatography time-of-flight mass-spectrometry, which resulted in robust detection of a total of 206 metabolites. Metabolic phenotypes of colon cancer and normal tissues were different at a Bonferroni corrected significance level of p=0.00170 and p=0.00005 for the first two components of an unsupervised PCA analysis. Subsequent supervised analysis found 82 metabolites to be significantly different at p<0.01. Metabolites were connected to abnormalities in metabolic pathways by a new approach that calculates the distance of each pair of metabolites in the KEGG database interaction lattice. Intermediates of the TCA cycle and lipids were found down-regulated in cancer, whereas urea cycle metabolites, purines, pyrimidines and amino acids were generally found at higher levels compared to normal colon mucosa.
This study demonstrates that metabolic profiling facilitates biochemical phenotyping of normal and neoplastic colon tissue at high significance levels and points to GC-TOF-based metabolomics as a new method for molecular pathology investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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