Distant Disease-free Survival In Patients Research Articles

Development of surgical concepts in rectal cancer resection and challenges in minimally invasive surgical proctectomy

Since the early 1900s there have been dramatic changes in the management of patients with rectal cancer. Surgical approaches initially performed for palliation, have now been adapted, modernised and undertaken as part of a multimodal approach. This has resulted in significant improvements in long-term oncological survival and patient quality of life. With the introduction of total mesorectal excision (TME) in the 1980's, and its global acceptance by the surgical community, local and distant disease-free survival in patients with rectal malignancy has significantly improved. Since the inception of minimally invasive surgery, laparoscopy has seen dramatic changes both in the evolution of technological advances and application in multiquadrant surgery for colorectal malignancy. Favorable short-term clinical benefits and long-term oncological equivalence from many multicentre randomized controlled trials in laparoscopic colonic cancer resection has led the colorectal surgical community to translate and adapt minimally invasive surgical (MIS) techniques for proctectomy in patients with rectal tumours. MIS proctectomy is technically challenging and is associated with a steep learning curve. Reported challenges in the literature continuously identify a group within three common themes which can be divided into patient/anatomical factors, tumour characteristics and the use of neoadjuvant therapies. Despite a large body of evidence highlighting efficacy of MIS in proctectomy, significant challenges exist in male patients with a narrow pelvis and distal tumors. Such patients are at increased risk of a poor surgical specimen, positive distal and circumferential resection margins (CRMs), and increased local recurrence. Despite advances in laparoscopy and robotic platforms, approaching such lesions from a “top down” approach expose the ongoing limitations to lower pelvic access. This technically challenging issue has led to the colorectal surgical community adopting previously taught MIS techniques to develop a “bottom up” transanal approach to TME, now known as transanal TME (taTME) in order to mitigate this increased margin risk.

The long-lasting anti-tumor activity of cisplatin affecting the sustainable systemic immune alteration may improve distant-disease free survival of triple-negative breast cancer in patients with a substantial residual tumor following preoperative chemotherapy: A retrospective analysis with translational research.

e12631 Background: Residual disease after preoperative chemotherapy is known to be a poor prognostic factor in triple-negative breast cancer (TNBC). Perioperative use of cisplatin (CDDP) is a well-known, standard treatment for most tumors except breast cancer. In this study, we explore the long-lasting anti-tumor activity of CDDP for TNBC patients. Methods: This research was based on consecutive study of seventy-nine previously untreated stage I–III TNBC patients treated with or without CDDP-based preoperative chemotherapy from 2007 to 2018 at the Kyoto University Hospital. We calculated the residual cancer burden (RCB) using the RCB calculator. All patients were sorted according to their RCB class: the pathological complete response (pCR), and RCB class I (minimal), II (moderate) or III (extensive). Distant disease-free survival (DDFS) was analyzed using the Kaplan-Meier method. Using mass spectrometry, we measured platinum concentrations in serum and normal breast tissue removed during surgery from patients treated with any platinum agents. We examined multiplex cytokine assays from serum sequentially, comparing CDDP and non-CDDP groups. Results: Forty-seven cases were treated with CDDP, and thirty-two did not have CDDP. The pCR rate was 53.2% for the CDDP group and 21.9% without CDDP. Patients with pCR and RCB class I were all distant disease-free. There was no significant difference between each RCB class using CDDP. However, patients belonging to RCB classes II and III with CDDP showed a better prognosis than the same RCB classes without CDDP (hazard ratio = 0.12). Platinum concentrations in serum were correlated with the time from the last dose of platinum agents, but platinum was even detected in serum two years after CDDP. No significant difference was found in the platinum concentrations of serum or normal breast tissue in the pCR and non-pCR groups. We also found that there were significant cytokine expression alteration related to T-cell infiltration only in the CDDP group one year after operation. It is suggested that CDDP may even affect the systemic immune alteration one year after operation. Conclusions: Our data shows that CDDP- based chemotherapy improves DDFS in patients with a substantial residual tumor. CDDP seems to sustain anti-tumor activity for a number of years and interaction with the systemic immune alteration.

Abstract P3-07-10: Prognostic value of neutrophil-lymphocyte ratio in early breast cancer patients with ER+/Her2 negative and its association with 21 gen recurrence score

Abstract Background: Breast cancer (BC) is a heterogeneous disease, around 70% of these tumors are hormone receptor (HR) positive. The 21 gene recurrence score (RS) is a prognosis tool to define disease-free-survival in patients with early-stage HR+/HER2- BC with negative and positive lymph nodes also because its predictive value is used to decide the kind of adjuvant systemic treatment. The ability of malignant cells to progress and subsequently metastasize is not entirely dependent on their own intrinsic cellular signaling pathways but also of complex interactions with the tumor microenvironment and the innate and specific immune system. A high neutrophil to lymphocyte ratio (NLR) has been associated with lower overall survival (OS), disease-free survival (DFS) and distant disease-free survival (DDFS). Because both tools have evidence to evaluate prognosis. We propose that NLR would be a faster and cheaper alternative to achieved prognosis in low/middle-income countries. Objective: 1)Evaluated the association between NLR and RS to predict disease-free survival and distant disease-free survival in patients with early-stage HR+/HER2- BC. 2)Define the prognosis value to DFS and DDFS of NLR in patients with HR+/HER2- BC. Methods: We collected data from 208 patients with HR+/HER2- early BC treated with surgery upfront and RS has done. The recorded variable used were tumor size, nuclear grade, lymph node status. Regarding HR status, estrogen receptor (ER) positive was mandatory and progesterone receptor (PR) was exploratory. Complete blood count (CBC) test was obtained after BC diagnosis and prior to breast surgery. NLR was calculated as absolute neutrophil count divided by absolute lymphocyte count. The cut-off value used was 2.5. RS of each patient was categorized into a low-risk (≤ 25) or high-risk (> 26). Disease-specific survival curves were calculated according to the Kaplan-Meier method and comparison was done with the log-rank test, the correlation between NLR and RS was assessed using Spearman’s rank correlation coefficient. Statistical analysis was performed by SPSS software v 23.0. Results: The median age was 61.1 years old (33-97), median tumor size 2,3 (0.5-5) cm, 92.8% were PR-positive, 71.5% had lymph node metastases (1-3), 159 (76%) patients had NLR < 2.5. There was no difference in DFS 91.8 months vs 93.7 months p=0.44 neither in DDFS 92.9 months vs 94.6 months p=0.30 between groups by NLR. NLR did not correlate significantly with RS (Spearman’s r= 0.08, p=0.23). Correlation among NLR a PR, lymph node status, nuclear grade, and tumor size, was not significant. Low RS was associated with a DFS of 96% vs 87.8% in high RS (p=0.049) Conclusions: We failed to demonstrate the prognostic value of NLR for DFS in HR+/HER2- early breast cancer. NLR does not correlate with RS so, RS remains to be the most useful prognostic factor in this population. Citation Format: Ivan Maldonado-Noboa, Paula Cabrera-Galeana, Claudia Arce-Salinas, María Elena Lara, Gerardo Cuamani-Mitznahuatl, Diego Ladron De Guevara, Adan Ordoñez, Enrique Bargallo-Rocha. Prognostic value of neutrophil-lymphocyte ratio in early breast cancer patients with ER+/Her2 negative and its association with 21 gen recurrence score [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-10.

Longer follow-up on cardiac safety and distant disease free survival of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab in patients with early-stage HER2-positive breast cancer.

540 Background: We previously reported the cardiac safety results and distant disease-free survival (DDFS) on a phase 2 trial of dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) in patients with early stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The incidence of congestive heart failure (CHF) was 1.4% both at a median follow-up of 2 and 7 years. Here, we report updated CHF and DDFS rates with longer follow-up. Methods: Patients were enrolled with HER2 overexpressed (immunohistochemistry 3+) or amplified (fluorescent in situ hybridization ratio > 2.0) disease, regardless of size or nodal status, and baseline left ventricular ejection fraction (LVEF) of > 55%. Patients (pts) received dd AC (60/600 mg/m2) q 2 weeks (w) x 4 →T (175 mg/m2) q 2 w x 4 with H (loading dose 4 mg/kg → 2 mg/kg q w during T → 6 mg/kg q 3 w for rest of 1 year); pegfilgrastim was administered after each chemotherapy cycle. LVEF monitoring with multigated acquisition scan occurred at baseline, months 2 (after AC), 6, 9, and 18 (after therapy completion). Results: From January 2005 to November 2005, 70 pts were enrolled; 2 (3%) and 68 (97%) were treated in neoadjuvant and adjuvant settings, respectively. In 68 pts treated in adjuvant setting, 40 (60%) and 27 (40%) had node-positive and node-negative disease, respectively. The median age was 49 years old (range 27-72); 55 (79%) had hormone-receptor positive disease, 11 (16%) had hypertension, and 21 (30%) had left sided radiation. The median baseline LVEF was 68% [range, 55%-81%]). With a median follow-up of 10.9 yrs, there was no additional CHF event. Therefore, the cumulative incidence of CHF remains to be 1.4% (95% confidence interval [95% CI], 1.36%- 7.7%). The 9 and 10 year DDFS rates were 89% (95% CI, 78%-94%) and 87% (95% CI 75%-93%), respectively. Conclusions: Longer follow-up of this study has demonstrated that ddAC →TH is associated with a low risk of CHF and promising DDFS in patients with early-stage HER2-positive breast cancer.

Impact of the response of primary tumor to preoperative chemotherapy and anti-HER2 therapy on survival of HER2-positive breast cancer patients

To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer. The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively. Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028). Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.

Abstract P4-09-21: Dual expression of aquaporin 3 and 5 in patients with early breast cancer

Abstract Background: We reported separately that AQP5 or AQP3 expression in tumor tissue may predict survival after surgery for the specific types of early breast cancer (EBC). However, there is no definitive evidence for the role of dual expression of the two AQPs. Therefore, the current study focused the association and its prognostic impact of their tumoral expressions in the same patients. Patients and Methods: AQP3 and AQP5 expressions were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 447 EBC patients who underwent surgery between 2003 and 2008 as described in previous studies. Patients were divided into 4 subgroups based on AQP3 and AQP5 expressions: group1 for (-/-), group2 for (-/+), group 3 for (+/-), and group 4 for (+/+), respectively. Results: Among 477 patients, the number of patients for each group was as follows: group 1 (n=193, 43.2%), group 2 (n=74, 16.6%), group3 (n=110, 24.6%) and group 4 (n=70, 15.7%), respectively. In the current study a positive correlation was identified between AQP3 and 5 expressions (P=0.017 by a χ2- test) in particular for HER2- overexpressing and ER-positive tumors (P=0.009 and 0.044, respectively). Multivariate survival analysis showed that dual expression of AQP3 and AQP5 was a negative prognostic factor for relapse-free or distant disease-free survival for patients with HER2-overexpressing EBC (HR=3.107 and 3.683; P=0.043 and 0.027, respectively), statistically more prominent compared in case with AQP3 expression alone (HR=3.137 and 2.784; P=0.036 and 0.070, respectively). Conclusion: Dual expression of AQP3 and AQP5 in tumor tissue may be considered as a potential prognostic marker in patients with HER2-overexpressing EBC after curative surgery. Citation Format: Lee SJ, Chae YS, Kwon TJ, Chung JH, Lee J, Jung JH, Kim WW, Park HY, Jeong JY, Park S-H, Park S. Dual expression of aquaporin 3 and 5 in patients with early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-21.

Long‐term cardiac safety and outcomes of dose‐dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab with and without lapatinib in patients with early breast cancer

The authors have previously reported 2 consecutive phase 2 trials in patients with early breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2) to assess the feasibility of incorporating anti-HER2 therapies into dose-dense (dd) chemotherapy regimens. The incidence of congestive heart failure (CHF) at a median follow-up of 2 years was 1.4% and 3.2%, respectively. In trial A, patients received dd doxorubicin and cyclophosphamide (AC)→paclitaxel (T) (each given every 2 weeks) × 4 with trastuzumab (H) given × 1 year. In trial B, weekly T (weekly × 12) was substituted for ddT and lapatinib × 1 year was added. Herein, the authors report the longer-term incidence of CHF and distant disease-free survival (DDFS). From January 2005 to May 2008, 165 patients enrolled (median age, 46 years, with a median left ventricular ejection fraction of 68% [range, 52%-81%]), 17%of whom had previous hypertension. With a median follow-up of 84 months (trial A) and 57 months (trial B), 1 additional patient developed CHF. Therefore, the cumulative incidence of CHF was 1.4% (95% confidence interval [95% CI], 1.36%-7.7%) for trial A and 4.2% (95% CI, 4.2%-10.4%) for trial B. The 5-year DDFS for trials A and B was 92% (95% CI, 83%-97%) and 89% (95% CI, 81%-94%), respectively. Longer follow-up of these 2 studies has demonstrated that ddAC→TH only or with lapatinib is associated with a low risk of CHF and promising DDFS in patients with early breast cancer.

Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer

BackgroundThe aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer.MethodsUsing a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein.Results1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor.ConclusionsRunning high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.

American Joint Committee on Cancer Tumor–Node–Metastasis Stage After Neoadjuvant Chemotherapy and Breast Cancer Outcome

Response to neoadjuvant chemotherapy is used as an intermediate endpoint for breast cancer relapse and survival. Most breast cancer response classification systems use pathologic complete response, either alone or in conjunction with clinical assessments, to categorize response. We examined the ability of the revised 2003 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, which considers both the number of involved axillary lymph nodes and the extent of tumor in the breast to predict patient survival after neoadjuvant chemotherapy for breast cancer. We assessed the pathologic stage of residual tumor in 132 patients with nonmetastatic breast cancer after they had undergone neoadjuvant chemotherapy and examined the association between AJCC TNM stage and subsequent distant disease-free survival and overall survival. All statistical tests were two-sided. At a median follow-up of 5 years, pathologic stage in the surgical specimens after neoadjuvant chemotherapy using the revised AJCC system was strongly associated with both distant disease-free survival and overall survival. A higher pathologic stage of residual tumor after neoadjuvant chemotherapy was associated with a statistically significant lower rate of distant disease-free survival (stage 0: 95%, stage I: 84%, stage II: 72%, and stage III: 47%; Ptrend < .001). The 5-year distant disease-free survival for patients with residual stage IIIC tumors was only 18% (95% CI = 0% to 36%). Classification of residual tumor in the breast and axillary surgical specimens after neoadjuvant chemotherapy using the revised AJCC TNM system is useful for predicting distant relapse and survival.

Sentinel lymph node biopsy in melanoma patients: the medical oncologist's perspective.

With the advent of sentinel node (sN) biopsy in melanoma patients, elective lymph node dissection (ELND) can be considered an exceeded procedure. Regardless of the possible therapeutic benefits, sN biopsy efficiently predicts prognosis avoiding the morbidity rate of ELND. The importance of the sN is underlined by multivariate analyses, which show that the sN status represents the most important prognostic factor influencing disease-free and distant disease-free survival in patients with stage I and II melanoma. Moreover, sN biopsy provides a minimally invasive method for identifying those patients with subclinical nodal metastasis who actually have stage III disease, with a very high risk of occult distant metastases and who may benefit by adjuvant therapy.

Peritoneal and serum tumor markers predict recurrence and survival of patients with resectable gastric cancer.

BACKGROUND: Laparoscopy has become a useful adjunct for the staging of gastric cancer; yet, other than standard TNM staging, few additional variables can be used to predict survival. This study evaluated the utility of serum and peritoneal tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]-125) as predictors of locoregional recurrence and distant disease-free survival in patients with gastric cancer.METHODS: During the period June 1990 to February 1994, 86 patients with gastric cancer were evaluated and deemed resectable by preoperative imaging studies. Serum levels of CEA and CA-125 were determined, and all patients underwent laparoscopic staging. Peritoneal washings were obtained from all patients, and 56 of these samples were evaluated for levels of CEA and CA-125.RESULTS: Sixteen (19%) of the 86 patients were found to have metastatic disease at laparoscopy; 67 of the remaining 70 patients underwent potentially curative gastrectomy. Serum CEA and CA-125 levels were predictive of survival in the entire group of patients. In patients who underwent curative gastrectomy, serum CEA predicted survival, whereas peritoneal CA-125 predicted peritoneal recurrence.CONCLUSIONS: Elevated serum levels of CEA and CA-125 are predictive of decreased survival in patients with gastric cancer. Furthermore, determination of peritoneal CA-125 helps to identify those patients at an increased risk for recurrent peritoneal disease.