Local-regional Recurrence Research Articles

Development and Validation of a MicroRNA Signature Predictive of Local-Regional Recurrence and Overall Survival after Resection of Pancreatic Ductal Adenocarcinoma (PDAC)

Prognosis for PDAC remains poor despite oncologic resection and adjuvant chemotherapy, with local-regional recurrence (LRR) rates as high as 60-70% at 2 years and 5-year overall survival (OS) of less than 30%. The use of postoperative radiotherapy (RT) is controversial, and identification of novel molecular markers may assist in selecting patients at high risk for LRR who might benefit from RT. We hypothesized we could identify a novel microRNA (miRNA) expression profile associated with LRR and OS in resectable PDAC. We isolated total RNA from formalin-fixed, paraffin-embedded tumor and adjacent normal tissue from patients who underwent surgery and adjuvant chemotherapy at 3 institutions. We created equal-sized training and validation cohorts balanced by institution and LRR events. MiRNA expression was analyzed using a multiplex analysis platform human miRNA v3 platform. Using mixed modeling, we identified miRNAs differentially expressed in tumor and normal tissue in the full dataset and used elastic net modeling to identify miRNAs predictive of LRR and OS in the training dataset. Risk scores were generated using Cox coefficients for each miRNA. For multivariable analysis (MVA), we evaluated the association of risk score with LRR and OS using Cox proportional hazards, accounting for age, pathologic T and N stage, histologic grade, postoperative CA 19-9, and margin status. For Kaplan-Meier analysis, each cohort was dichotomized by its median risk score. There were 90 patients in the training and 93 patients in the validation cohort. Most (96.2%) patients received no RT. Risk score predicted LRR in the training (hazard ratio [HR] = 1.4; 95% confidence interval [CI] 1.1 - 1.8; p = 0.002) and validation cohort (HR = 1.3; 95% CI 1.0 - 1.6; p = 0.046). It did not predict OS in the training cohort (p = 0.4), but was predictive in the validation cohort (HR = 1.2; 95% CI 1.0 - 1.4; p = 0.04). After dichotomization, binary risk score predicted LRR in the training (HR = 3.3; 95% CI 1.5 - 7.0; p = 0.002) and validation cohort (HR = 2.1; 95% CI 1.1 - 4.0; p = 0.03). It trended toward association with OS in the training cohort (HR = 1.6; 95% CI 0.98 - 2.5; p =0.058) and was significant in the validation cohort (HR = 1.6; 95% CI 1.0 - 2.5; p = 0.04). On MVA, binary risk score independently predicted LRR (HR = 3.7; 95% CI 1.2 - 11.2; p = 0.02) and OS (HR = 2.1; 95% CI 1.0 - 4.4; p = 0.039) in the training cohort. In the validation cohort, there was a trend toward association with LRR (HR = 2.2; 95% CI 0.98 - 5.1; p = 0.056) and OS (HR = 1.8; 95% CI 0.9 - 3.4; p = 0.09). Using a multi-institutional dataset, we identified and validated a miRNA signature associated with LRR and OS in patients with resectable PDAC. This signature may be useful in selecting patients at higher risk of LRR who would benefit from adjuvant RT, and should be tested in prospective clinical trials.

Chest Wall and Supraclavicular/Infraclavicular Nodal Region are Common Sites of Locoregional Recurrence for Women with Breast Cancer after Mastectomy Irrespective of TN Stage or Molecular Subtypes

To analyze the failure patterns of locoregional recurrence (LRR) and identify the prognostic factors for local recurrence (LR) and regional recurrence (RR) in breast cancer patients after mastectomy. Between 1999 and 2014, 7207 women with breast cancer after mastectomy and axillary dissection were analyzed. All didn’t receive postmastectomy radiotherapy (PMRT). 4671 (64.8%) had pT1-2N0 disease (low-risk), 2078 (28.8%) had pT1-2N1 disease (intermediate-risk) and 458 (6.4%) were defined as high-risk, which included 360 with pT3-4 or pN2-3 disease and 98 pT1-2N1 after neoadjuvant chemotherapy. Among the 5427 patients who had sufficient information to construct molecular subtype, there were 2451 (45.2%) luminal A, 579 (10.7%) luminal B-Her2 negative, 814 (15.0%) luminal B-Her2 positive, 593 (10.9%) Her2 enriched, and 990 (18.2%) triple negative (TN). The distribution of accumulated LRR was analyzed. The LR and RR rates were estimated by the Kaplan-Meier method, and the differences were compared with Log-rank test. Multivariate analysis was performed using Cox logistic regression analysis. With a median follow-up of 62.9 months (6.0-194.6), 481 patients had LRR, including chest wall in 225 (46.8%), supraclavicular/infraclavicular nodes (SCN) in 242 (50.3%), axilla in 96 (20.0%) and internal mammary nodes (IMN) in 52 (10.8%) patients. For LRR patients with low, intermediate and high risk group, 93 (54.1%), 83 (44.9%), 69 (55.6%) had chest wall recurrence, 68 (39.5%), 110 (59.5%), 64 (51.6%) had SCN recurrence, 27 (15.7%), 37 (20.0%), 32 (25.8%) had axilla recurrence, and 28 (16.3%), 20 (10.8%), 4 (3.2%) had IMN recurrence. For LRR patients with luminal A, luminal B-Her2 negative, luminal B-Her2 positive, Her2-enriched, and TN tumors, 48 (45.3%), 23 (56.1%), 25 (43.1%), 25 (57.2%), 61 (58.1%) had chest wall recurrence, 51 (48.1%), 23 (56.1%), 32 (55.2%), 33 (62.3%), 51 (48.6%) had SCN recurrence, 21 (19.8%), 10 (24.4%), 13 (22.4%), 9 (17.0%), 22 (21.0%) had axilla recurrence, and 9 (8.5%), 7 (17.1%), 6 (10.3%), 7 (13.2%), 14 (13.3%) had IMN recurrence. The median interval to LR and RR was 51.6 and 29.2 months. In multivariate analysis, age (≤45 years vs. >45 years), tumor location (inner quadrant vs. other quadrants), T stage (T3-4 vs. T1-2), N stage (pN3 vs. pN2 vs. pN1 vs. pN0), hormone receptor status (negative vs. positive) were significant prognostic factors for both LR and RR (p < 0.05). In breast cancer after mastectomy without PMRT, both chest wall and supraclavicular/infraclavicular nodal region are common sites of LRR, irrespective of TN stage or molecular subtypes. The prognostic factors for LR and RR are similar, which indicates that chest wall and supraclavicular/infraclavicular nodal irradiation should be considered in all patients who planned to receive PMRT.

Shorter Half-Life Clearance of Plasma EBV DNA Is a Significant Prognostic Factor of Non-Metastatic Nasopharyngeal Carcinoma Treated with Radical Intensity-Modulated Radiation Therapy

Plasma Epstein-Barr virus (EBV) DNA has been adopted widely in diagnosis, treatment monitoring and post-treatment surveillance of nasopharyngeal carcinoma (NPC). However, the prognostic role of its plasma clearance in the modern era when intensity-modulated radiotherapy (IMRT) and the 8th edition of AJCC/UICC TNM Staging Classification are fully implemented. We investigated if the half-life clearance of plasma EBV DNA could be an early prognosticator of survival during radical IMRT with or without chemotherapy for previously untreated non-metastatic NPC. Forty-four patients with previously untreated non-metastatic NPC were prospectively recruited and treated with radical IMRT and concurrent chemotherapy +/- induction/adjuvant chemotherapy from 2014 to 2018. All had their plasma EBV DNA measured immediately before treatment followed by weekly schedules until it was undetectable in two consecutive measurements (i.e. 0 copies/ml), as determined by real-time quantitative polymerase chain reaction. Cox regression models were employed to identify prognostic factors of survival. The overall stage distribution was: stage II in 9 (20.4%); stage III in 21 (47.7%) and stage IVA in 14 (31.8%) patients. After a median follow-up of 18.4 months (range 3.4–57.1 months), 2 patients (4.5%), 1 (2.3%) and 4 (9.1%) experienced local recurrences, regional recurrence and distant metastases respectively. Four patients (9.1%) died and all were related to NPC progression. The mean half-life of plasma EBV DNA clearance was 9.82 days. Patients were dichotomized according to the half-life clearance: those with half-life of >15 days had a significantly worse 2-year progression-free survival (PFS) (84.2% vs. 60.0%; p=0.001) and distant metastasis-free survival (DMFS) (94.7% vs. 60.0%; p<0.001) when compared to those with a shorter half-life. Univariable and multivariable analyses demonstrated that age (HR 1.10; 95% CI 1.01–1.19; p=0.026) and half-life (>15 days) were prognostic of PFS (HR 11.13; 95% CI, 2.13–58.11; p=0.007), while half-time (>15 days) was the only prognostic factor of DMFS (HR 14.24; 95% CI, 2.53–79.80; p=0.003). The half-life clearance of plasma EBV DNA was a significant prognostic factor in patients with non-metastatic NPC treated in the modern era. Earlier active surveillance with this relatively non-invasive plasma monitoring tool should be adopted, leading to more prompt subsequent imaging and intensified treatment especially for those who have a suboptimal clearance during their radical treatment.

Local Regional Recurrence rates for pT1-2 N0 Oral Tongue Squamous Cell Carcinoma Treated with Surgery Alone at a High Volume Academic Multidisciplinary Head and Neck Oncology Program

To report the treatment outcomes of definitive surgery without adjuvant radiation or chemotherapy for patients with pT1-T2 N0 oral tongue squamous cell carcinoma (OTSCC). We conducted a retrospective analysis of patients with pT1-T2N0 (AJCC 7th edition) OTSCC treated at a single academic institution from 2008 to 2018. All patients had definitive surgery at one academic institution with no adjuvant treatment. Two year actuarial rates of local control (LC), regional control (RC), local regional control (LRC), cancer specific survival (CSS), and overall survival (OS) were calculated. Sixty six patients were included in this analysis. The median follow up was 33.9 months (1.2 – 121.8). When using updated staging, 61.5% had pT1 disease, 29.2% had pT2 disease, and 7.7% had pT3 disease (had been pT2 in 7th edition staging). Zero patients had positive margins, 27 had close margins, 1 had positive perineural invasion, 3 had positive LVI, and 18 had DOI > 4mm (13 patients did not have DOI information). Fourteen (14) patients had recurrence: 11 local and 7 regional (4 had both). The 2 year LC, RC, LRC, CSS, and OS were the following: 86%, 95%, 82%, 96%, and 96%. Of the patients with recurrence, 64% (9) were pT1, 21% (3) were pT2, and 14% (2) were pT3. The majority of the patients had elective neck dissection (50 patients, 76%) and specifically 71% of those who recurred had elective neck dissection. No pathological feature was found to be significantly correlated with recurrence. Salvage retreatment was successful for 9 of the 14 recurrences. Recurrence rates after surgery alone for patients with pT1-2N0 OTSCC treated at a high volume academic program are not insignificant (18%), however salvage retreatment is possible. It is reasonable to consider postoperative radiotherapy in patients with pT1-T2N0 OTSCC.

Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer.

Despite the overall success of radiotherapy, a significant number of patients develop radioresistance, which leads to local regional recurrence and distant metastasis. We studied whether repeated radiation treatment promotes androgen-independent survival of prostate cancer (PCa) cells and their metastatic potential. We also studied whether glucocorticoid receptor (GR) increase in radioresistant cells is associated with acquisition of these aggressive characteristics. Radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) PCa sublines were developed by repeated radiation treatments of parental cells. Levels and activations of androgen receptor (AR) and GR in radioresistant PCa cells and respective parental cells were investigated in quantitative real-time polymerase chain reaction/Western blot analyses and immunofluorescence staining. Androgen-independent survival of radioresistant cells was tested in in vitro cell growth assays and the castration-resistant survival of these cell-derived tumors were investigated in mouse xenografts. Higher GR levels, but lower AR levels were detected in radioresistant cells than in parental cells. Radiation-induced GR upregulation was associated with increased intracellular cyclic adenosine monophosphate. As a consequence of GR activation, LNCaPR18 cells survived well in an androgen-depleted culture condition while parental cells could not. Results of in vivo mouse studies showed survival of LNCaPR18 cell-derived tumors in castrated mice while parental cell-derived tumors regressed. The growth of LNCaPR18 cell-derived tumors in castrated mice was impaired when treated with the anti-GR agent mifepristone. In experiments with C4-2/C4-2R26 cell sets, GR activation in C4-2R26 cells increased their metastatic potential. GR activation in radioresistant cells mediates androgen independence and facilitates PCa progression.

Effectiveness of image-guided radiotherapy for rectal cancer patients treated with neoadjuvant concurrent chemoradiotherapy: A population-based propensity score-matched analysis.

The effects of image-guided radiotherapy (IGRT, an advanced RT technology) have been debated in the literature. We compared the outcomes of locally advanced rectal cancer (LARC) patients treated with neoadjuvant concurrent chemoradiotherapy (NCCRT; with vs without IGRT) in a large population-based propensity score (PS)-matched analysis. We identified LARC patients diagnosed between 2007 and 2015 via the Taiwan cancer registry (TCR) and constructed a PS-matched cohort to balance observable potential confounders. Outcomes (R0 resection, overall survival, incidence of local regional recurrence [ILRR], rectal cancer mortality [IRCM], other cancer mortality [IOCM] and cardiovascular mortality [ICVM]) were obtained from TCR and the national death registry. We compared the hazard ratio (HR) of death and other endpoints between IGRT and non-IGRT groups. We performed supplementary analysis (SA) to evaluate the robustness of these results in a subgroup, taking an additional potential confounder into account. Our study population comprised of 586 patients that were balanced with regard to observed covariables. There was no significant difference in HR for death (0.99; 95% confidence interval 0.70-1.39; P=0.94) between IGRT and non-IGRT groups. There were also no significant differences in R0 resection, ILRR, IRCM, IOCM or ICVM. The results of our SA were consistent with these findings. For LARC patients treated with NCCRT, the treatment outcome was not significantly different among patients treated with and without IGRT. Further study is needed to clarify these results with consideration to additional potential confounding factors and toxicity profiles at endpoints.

Study on safety of adjuvant radiotherapy concurrent with weekly chemotherapy for stage ⅡB-ⅣA esophageal carcinoma after radical resection

Objective: To evaluate the tolerability and short-term efficacy of chemo-radiotherapy in 125 patients with stage ⅡB-ⅣA esophageal carcinoma after radical resection. Methods: We retrospectively evaluated the rate of completion, toxicity and survival of patients undergoing adjuvant concurrent chemo-radiotherapy after radical resection of esophageal carcinoma from January 2004 to December 2014 in our institution. The survival rate was determined by the Kaplan-Meier method and analyzed using the log-rank test. Multivariate prognostic analysis was performed using the Cox proportional hazard model. Results: 122 patients received more than 50 Gy dose (97.6%). A total of 52 patients received more than 5 weeks chemo-radiotherapy (41.6%), while 73 patients underwent only 1-4 weeks (58.4%). The median following up was 48.4 months. 8 patients lost follow up (6.4%). The 1-year and 3-year overall survival rate were 91.6% and 57.0%, respectively, with a median survival time of 64.4 months. The 1-year and 3-year disease free survival rate were 73.2% and 54.3%, respectively, with a median disease free survival time of 59.1 months. The most common acute complications associated with chemo-radiotherapy were myelosuppression, radiation esophagitis and radiation dermatitis, the majority of which were Grade 1-2. Of the 125 patients, there were 59 cases of recurrence, including 23 cases with local regional recurrence, 26 cases with hematogenous metastasis, and 8 cases with mixed recurrence. Univariate analysis showed that the numbers of concurrent chemotherapy was associated with the overall survival (P=0.006). But receiving more than 5 weeks was not the prognostic factor compared to 1 to 4 weeks chemotherapy (P=0.231). Multivariate analysis showed that only the numbers of concurrent chemotherapy was an independent prognostic factor (P=0.010). Conclusions: Postoperative radiotherapy concurrent with weekly chemotherapy could improve the overall survival and decrease the recurrence for stage ⅡB-ⅣA esophageal carcinoma after radical resection. However, the completion rate of chemotherapy was low, so it was necessary to explore reasonable regimens to improve the completion rate and carry out prospective randomized controlled trial.

Deep Learning Predicts Lung Cancer Treatment Response from Serial Medical Imaging.

Tumors are continuously evolving biological systems, and medical imaging is uniquely positioned to monitor changes throughout treatment. Although qualitatively tracking lesions over space and time may be trivial, the development of clinically relevant, automated radiomics methods that incorporate serial imaging data is far more challenging. In this study, we evaluated deep learning networks for predicting clinical outcomes through analyzing time series CT images of patients with locally advanced non-small cell lung cancer (NSCLC).Experimental Design: Dataset A consists of 179 patients with stage III NSCLC treated with definitive chemoradiation, with pretreatment and posttreatment CT images at 1, 3, and 6 months follow-up (581 scans). Models were developed using transfer learning of convolutional neural networks (CNN) with recurrent neural networks (RNN), using single seed-point tumor localization. Pathologic response validation was performed on dataset B, comprising 89 patients with NSCLC treated with chemoradiation and surgery (178 scans). Deep learning models using time series scans were significantly predictive of survival and cancer-specific outcomes (progression, distant metastases, and local-regional recurrence). Model performance was enhanced with each additional follow-up scan into the CNN model (e.g., 2-year overall survival: AUC = 0.74, P < 0.05). The models stratified patients into low and high mortality risk groups, which were significantly associated with overall survival [HR = 6.16; 95% confidence interval (CI), 2.17-17.44; P < 0.001]. The model also significantly predicted pathologic response in dataset B (P = 0.016). We demonstrate that deep learning can integrate imaging scans at multiple timepoints to improve clinical outcome predictions. AI-based noninvasive radiomics biomarkers can have a significant impact in the clinic given their low cost and minimal requirements for human input.

The impact of epidermal growth factor receptor mutations on the efficacy of definitive chemoradiotherapy in patients with locally advanced unresectable stage III non-small cell lung cancer: a systematic review and meta-analysis

ABSTRACTObjectives: To investigate the impact of EGFR mutations on the efficacy of definitive chemoradiotherapy (CRT) in patients with locally advanced unresectable stage III NSCLC.Methods: PubMed and EMBASE were searched for eligible studies. Efficacy outcomes included objective response rate (ORR), overall disease progression, local-regional recurrence (LRR), distant progression (DP), brain metastasis, progression-free survival (PFS) and overall survival (OS). Meta-analysis was performed when relevant data were available.Results: The authors identified seven eligible studies including 695 patients. No significant difference was detected in ORR (Risk Ratio [RR] 1.13, 95% confidence interval [CI] 0.91–1.39, P = 0.28) and overall disease progression (RR 1.06, 95% CI 0.95–1.19, P = 0.29) between EGFR-mutant and EGFR-wild-type groups. EGFR-mutant group had significantly lower LRR (RR 0.49, 95% CI 0.33–0.72, P < 0.01), higher DP (RR 1.36, 95% CI 1.18–1.55, P < 0.01) and higher brain metastasis (RR 2.48, 95% CI 1.46–4.20, P < 0.01) than the EGFR-wild-type group. No sufficient data were available to perform pooled analysis regarding PFS and OS.Conclusion: For patients with locally advanced unresectable stage III NSCLC treated with definitive CRT, the presence of EGFR mutations may be indicative of lower locoregional recurrence and higher distant progression, especially brain metastasis.

Mammography, US, and MRI to Assess Outcomes of Invasive Breast Cancer with Extensive Intraductal Component: A Matched Cohort Study.

Background An extensive intraductal component (EIC) in breast cancer is an independent risk factor for local recurrence after surgery, especially in young, premenopausal women. Few studies have analyzed long-term outcomes or imaging features of EIC-positive breast cancer. Purpose To assess the prognostic value of EIC on recurrence-free and overall survival in breast cancer and evaluate imaging features of EIC-positive breast cancer by using mammography, US, and MRI. Materials and Methods A retrospective study of 6816 consecutive women with surgically diagnosed invasive breast cancer between January 2007 and December 2012 was performed. After individual matching, women were allocated into either an EIC-positive or an EIC-negative group. Imaging factors associated with prognosis were investigated. The recurrence-free and overall survival rates were compared. Univariable and multivariable analyses were performed to analyze the effect of EIC. Results Among 6136 included women (mean age, 48.9 years ± 9.8), 1800 EIC-positive and 4336 EIC-negative breast cancers were identified. After matching according to EIC presence was performed, 1551 women were allocated into each group. The mean follow-up period was 79.9 months. The local-regional recurrence rate in the EIC-positive group was higher than that in the EIC-negative group (39.4% [63 of 160] vs 25.5% [37 of 145]; P = .001). However, there were no significant differences in total recurrence rate (hazard ratio [HR]: 1.2; 95% confidence interval [CI]: 0.9, 1.4; P = .21) or death (HR: 1.1; 95% CI: 0.8, 1.5; P = .45). EIC was not a significant independent factor for recurrence-free survival (HR: 1.1; 95% CI: 0.9, 1.4; P = .45) or death (HR: 1.1; 95% CI: 0.8, 1.6; P = .44) in multivariable analyses. Calcification and non-mass lesions were more commonly seen at US and MRI in the EIC-positive group than in the EIC-negative group (P < .001). Conclusion The presence of an extensive intraductal component in women with invasive breast cancer did not affect overall survival or recurrence-free survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Eby in this issue.

Factor analysis of diagnosis and surgical treatment of local regional recurrence in breast cancer patients

Objective: To analyze the association between clinicopathological factors and clinical diagnosis, treatment and surgery of local regional recurrence (LRR) in breast cancer. Methods: A retrospective study was done to evaluate consecutive 7 823 breast cancer LRR cases between January 2009 and August 2018 at Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine. A total of 108 LRR patients were enrolled: 35 cases (32.4%) with ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery, 40 cases (37.0%) of chest wall recurrence (CR), and 33 cases (30.6%) with regional lymph node recurrence (LNR). All patients were female, aged from 26 to 83 years with a mean of 49 years. Clinicopathological factor and its relationship with different sites of LRR and following surgical choice were analyzed by χ(2) test, rank-sum test and Logistic regression. Survival analysis were performed between different LRR patterns and whether undergoing second surgery. Kaplan-Meier survival curves and Log-rank tests demonstrated the distribution of overall survival. Results: Both univariate analysis and multivariate analysis found that axillary lymph nodes (ALN) status (OR=7.27, 95% CI: 1.30 to 40.53, P=0.042) and disease-free interval (OR=0.18, 95% CI: 0.06 to 0.60, P=0.013) were related to different site of LRR. Compared with patients with IBTR, LNR and CR patients had a higher rate of ALN metastasis and a shorter disease-free interval. A total of 36 LRR patients underwent following surgery. In univariate analysis, initial ALN surgery (χ(2)=16.705, P=0.001), pathological type (χ(2)=7.047, P=0.03), ALN status (χ(2)=10.812, P=0.002), disease-free interval (χ(2)=6.118, P=0.023) and LRR site(χ(2)=19.328, P=0.000) were associated with surgical treatment for LRR patients. Multivariate analysis demonstrated that only site of LRR was independently associated with surgery (OR=0.17, 95% CI: 0.05 to 0.65, P=0.024). The 5-year overall survival was 100% and 60.1% (P=0.018) for LRR patients treated with surgery or not. Furthermore, CR patients had significantly worse overall survival than LNR and IBTR patients, with 5-year overall survival 53.1%, 73.5%, and 100% respectively (P=0.021). Conclusions: Initial lymph nodes metastasis and disease-free interval are associated with different site of LRR. LRR site significantly influenced following surgery choice after LRR, which are both related with overall survival after LRR.

Surgical Therapy for Women with Multiple Synchronous Ipsilateral Breast Cancer (MIBC): Current Evidence to Guide Clinical Practice

Based on retrospective, historic data, surgeons have long recommended mastectomy as the surgical approach for women with multiple ipsilateral synchronous (multifocal or multi-centric) breast cancer (MIBC). In the modern era, however, local recurrence rates have significantly decreased due to improved imaging techniques and earlier detection through breast cancer screening, more accurate delivery of radiation, and the advent of targeted systemic therapies. Given the significant non-surgical advancements in the field of breast cancer care, the role of maximally invasive surgery in improving breast cancer outcomes has diminished. This raises the question as to whether the routine recommendation for mastectomy in MIBC is rooted in current evidence or archaic data. This review summarizes data regarding surgical options for women with MIBC. The incidence of MIBC is increasing as a result of improved imaging modalities and the use of breast MRI for breast cancer screening and staging. MIBC tends toward more aggressive biology and higher rates of nodal positivity but recent data contradict the notion that more aggressive surgery improves outcomes. Retrospective studies and meta-analyses performed in the current era of targeted therapy and more sensitive breast cancer detection have demonstrated equivalent rates of local regional recurrence (LRR) in women with MIBC undergoing breast-conserving therapy (BCT) when compared stage to stage with women with unifocal disease. Alliance Z11102, the first national, prospective trial of breast conservation in the MIBC population in the USA, demonstrated the feasibility of BCT in this patient population with acceptable rates of conversion to mastectomy in the MIBC cohort. Prospective data regarding LRR and cosmetic outcomes for women undergoing BCT from completed clinical trials continue to mature, and new randomized clinical trials investigating the biology and treatment of MIBC are under design. The incidence of MIBC is increasing due to screening mammography, improved quality of imaging, and the utilization of breast MRI for breast cancer screening and staging. Local regional recurrence rates in women with unifocal disease have decreased due to earlier detection and improved regional and systemic therapy. As adjuvant therapy improves, the extent of surgery is less impactful on LRR and long-term survival. Current data demonstrate acceptable LRR in women undergoing BCT for MIBC for whom negative surgical margins are achieved and appropriate adjuvant therapy is administered. While additional prospective data regarding biology, LRR, cosmesis, and long-term survival in women with MIBC continue to be collected, current evidence supports the role of patient choice in deciding between breast conservation and mastectomy in this population.

Diagnosis and treatment for unexpected gallbladder carcinoma(a retrospective study of 45 cases)

Objective: To investigate the rationale for appropriate diagnostic methods and treatment protocols for unexpected gallbladder carcinoma(UGC). Methods: The clinical and pathological data of 45 patients with UGC admitted at Department of General Surgery, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine,from January 2008 to December 2017 were retrospectively collected and analyzed.There were 11 males(28.9%) and 34 females(71.1%),aged 68 years(range:27 to 68 years).And there were 20 cases who aged above 70 years. Twenty-four cases were diagnosed preoperatively as cholecystolithiasis plus chronic cholecystitis.Ten cases were diagnosed preoperatively as cholecystolithiasis plus actue cholecystitis.Six cases were diagnosed preoperatively as cholecystolithiasis plus choledocholith.Six cases were admitted because of gallbladder polyp and 1 case was admitted because of gallbladder adenomyomatosis. Results: Thirty-four patients with UGC received radical surgery.Among them,11 patients experienced postoperative complication and no posterative mortality occoured during hospital stay.Thirteen patients were diagnosed with T1b UGC, the harvested lymph node of Nx, N0, N1 and N2 was 2, 9, 1 and 1, respectively.In addition, 2 cases were identified to have local-regional tumor recurrence during our rescue radical surgery.The median overall survival time of the patients who did not receive radical surgery was 7 months(range:2-56 months).Nevertheless,the median overall survival time for patients diagnosed with T1, T2 and T3 tumors who received radical surgery, was 41 months(range: 19-82 months), 33.5 months(range: 31-36 months) and 17 months(range: 7-46 months), respectively. Conclusions: For patients with UGC, rescue radical surgery can achieve a better survival time.Furhtermore, our experience proved that rescue radical surgery for UGC is safe and feasible.Therefore,rescue radical surgery should be performed in patients with diagnose with UGC especially those T1b patients.

Patterns of locoregional failure in women with early-stage breast cancer treated by whole breast irradiation in the lateral isocentric decubitus position: Large-scale single-centre experience

PurposeThe purpose of this study was to evaluate locoregional control and describe the patterns of failure in patients with breast cancer receiving whole breast radiotherapy in the isocentric lateral decubitus position technique. Patients and methodsIn a series of 832 consecutive female patients with early-stage breast cancer including invasive and in situ tumours treated by breast-conserving surgery followed by three-dimensional conformal whole breast irradiation in the isocentric lateral decubitus position between 2005 and 2010, all patients who experienced locoregional recurrence were studied. Five-year recurrence-free and overall survival rates were calculated. Regional recurrence mapping patterns were also determined. ResultsThe median age of this series of 832 women was 61.5 years (range: 29–90 years). Various types of fractionation were used: 50Gy in 25 fractions (17.9%), 66Gy in 33 fractions (50Gy in 25 fractions to breast followed by sequential boost to tumour bed to a total dose 66Gy in 33 fractions.) (46.5%), 40Gy in 15 fractions or 41.6Gy in 13 fractions (26.1%) and 30Gy in 5 fractions (9.5%). With a median follow-up of 6.4 years, only 36 patients experienced locoregional recurrence and no association with the fractionation regimen was identified (P=0.2). In this population of 36 patients, 28 (3.3%) had “in-breast” local recurrences (77.8%), two had local recurrences and regional lymph node recurrence (5.6%), and six had regional lymph node recurrence only (in non-irradiated areas; 16.6%). The median time to recurrence was 50 months. Complete mapping of patterns of recurrences was performed and, in most cases, local recurrences were situated adjacent to the primary tumour bed. Cases of local recurrences presented a significantly lower distant metastasis rate (P<0.001) and had a significantly longer overall survival compared to patients with regional lymph node recurrence (P<0.001). However, multivariate Cox regression analysis showed that the site of recurrence had no significant impact on overall survival (P=0.14). ConclusionThe results of this study indicate a low local recurrence rate. Further careful follow-up and recording of recurrences is needed to improve the understanding of patterns of recurrence.

Circulating Tumour Cells (CTC), Head and Neck Cancer and Radiotherapy; Future Perspectives.

Head and neck cancer is the seventh most common cancer in Australia and globally. Despite the current improved treatment modalities, there is still up to 50–60% local regional recurrence and or distant metastasis. High-resolution medical imaging technologies such as PET/CT and MRI do not currently detect the early spread of tumour cells, thus limiting the potential for effective minimal residual detection and early diagnosis. Circulating tumour cells (CTCs) are a rare subset of cells that escape from the primary tumour and enter into the bloodstream to form metastatic deposits or even re-establish themselves in the primary site of the cancer. These cells are more aggressive and accumulate gene alterations by somatic mutations that are the same or even greater than the primary tumour because of additional features acquired in the circulation. The potential application of CTC in clinical use is to acquire a liquid biopsy, by taking a reliable minimally invasive venous blood sample, for cell genotyping during radiotherapy treatment to monitor the decline in CTC detectability, and mutational changes in response to radiation resistance and radiation sensitivity. Currently, very little has been published on radiation therapy, CTC, and circulating cancer stem cells (CCSCs). The prognostic value of CTC in cancer management and personalised medicine for head and neck cancer radiotherapy patients requires a deeper understanding at the cellular level, along with other advanced technologies. With this goal, this review summarises the current research of head and neck cancer CTC, CCSC and the molecular targets for personalised radiotherapy response.

Nipple Discharge After Nipple-Sparing Mastectomy With and Without Associated Pregnancy

BackgroundNipple-sparing mastectomies (NSMs) preserve the intact nipple, including nipple duct orifices. Retained orifices might remain patent and communicate with the underlying reconstruction. We report the incidence and outcomes of nipple discharge after NSM in pregnant and nonpregnant women. Patients and MethodsRetrospective review of all NSMs at our institution from June 2007 to June 2018 was performed. Subsequent pregnancies and nipple discharge were documented. Patient demographic, operative, histopathology, and cancer treatment data were collected. Descriptive analysis was performed for patients who developed nipple discharge. ResultsFrom June 2007 to June 2018, 2778 NSM procedures were performed in 1620 patients, with a mean age of 48 (range, 20-80) years. Fifteen hundred sixty-eight NSMs were therapeutic and 1210 were for risk reduction. Thirty-three subsequent pregnancies were observed in 27 patients, with a mean age of 33 (range, 26-42) years at NSM. Bilateral or unilateral discharge occurred in 6 of 27 (22%) postpartum patients and resolved spontaneously. At 54 months mean follow-up after NSM (range, 16-98 months) and 23 (range, 1-61) months after delivery, no local-regional recurrences were observed. In 1593 patients without subsequent pregnancy, there were 4 patients (0.25%) treated with bilateral NSM with subsequent unilateral watery nipple discharge. There was no evidence of associated malignancy on physical exam, imaging, or cytology, and with 55 to 110 months follow-up, no new or recurrent cancers have been observed. ConclusionDespite extensive removal of nipple and subareolar duct tissue during NSM, milky nipple discharge is possible postpartum. Watery, acellular discharge occurs rarely in nonpregnant patients. To date, no patient with discharge has developed a local recurrence or new breast cancer.

Prognostic Factors of Local-Regional Recurrence in Patients with Operable Breast Cancer in Asia: A Meta-Analysis.

BACKGROUND:Cause of recurrence of breast cancer is multifactorial. Also, the occurrence of breast cancer in Asian patients has some different factors from the recurrence of breast cancer in western countries.AIM:This study aims to determine the prognostic factors of local-regional recurrence in patients with operable breast cancer in Asia.METHODS:The authors conducted a meta-analysis of published research articles published in an online database of PubMed, ProQuest and EBSCO between January 2000 and July 2018. Pooled risk ratios (RR) were calculated using fixed and random-effect models. Data were processed by using Review Manager 5.3 (RevMan 5.3).RESULTS:This study reviewed 879 articles. There were 11 studies conducted a systematic review then continued by meta-analysis of relevant data with total patients involved were 5,213 patients. The prognostic factors found of local-regional recurrence in patients with operable breast cancer were Nodal (N) stage with the highest risk ratio (RR = 6.35 [95% CI 3.78-10.67]) followed by HER2 positive (RR = 2.14 [95% CI 1.16-3.97]), stage of cancer (RR = 1.82 [95% CI 1.44-2.31]), tumor size (RR = 1.55 [95% CI 1.04-2.31]), tumor grade (RR = 1.43 [95% CI 1.23-1.65]), PR status (RR = 0.65 [95% CI 0.48-0.88]) and the least was ER status (RR = 0.60 [95% CI 0.39-0.91]). Homogeneity of variance was found in N stage, tumor size and tumor grade for recurrence of operable breast cancer.CONCLUSION:This meta-analysis confirmed the correlation of N stage, HER2, stage of cancer, tumour size, tumour grade, ER and PR status with recurrence in patients with operable breast cancer in Asia.

Abstract ES7-3: Indications for radiation treatments after neoadjuvant chemotherapy while awaiting the results of clinical trials

Abstract Using systemic therapy prior to surgery has become an accepted standard for patients with lymph node-positive disease at presentation. Studies demonstrate that this approach can eradicate the disease in lymph nodes prior to local-regional interventions. This occurs particularly frequently for patients with HER2/neu-positive disease and to a relevant degree for those with triple negative disease. Patients with an excellent pathological response to treatment have improved outcomes compared to those with extensive residual disease. However, it is less clear whether local-regional therapies can be diminished or omitted in patients with an excellent pathological response. Accordingly, such questions are currently being investigated in phase III clinical trials. Unfortunately, local-regional therapeutic trials require long-term outcome data, particularly for the endpoints of distant disease control and overall survival. Therefore, the ongoing studies addressing whether regional lymph node radiation can be omitted in selected patients after neoadjuvant chemotherapy will not provide clinically useful information in the near term. This is unfortunate because such questions arise with a high degree of frequency in oncology practices. This topic has also become increasingly important because completed clinical trials indicate that regional lymph node radiation combined with treatment of the chest wall/breast improves the outcome of patients with pathologically positive lymph node(s) and who are treated with surgery first followed by adjuvant systemic therapy. While the sequencing of chemotherapy and surgery does not affect the risk of local-regional recurrence for populations of patients, it does affect an individual patient's risk. For example, patients with clinically stage II, lymph node-positive disease (who do not receive radiation) will have lower risk of local-regional recurrence if they achieve a pathological complete response to neoadjuvant chemotherapy compared to those with residual positive lymph nodes. This is also true for patients with clinical stage III disease, although patients with locally advance breast cancer have a high enough risk for local recurrence even with a complete pathological response to warrant adjuvant radiation. Based on the data outlined above, the current standard outside the setting of clinical protocols is to recommend regional lymph node radiation with chest wall/breast radiation for all patients with residual positive lymph nodes after neoadjuvant chemotherapy and all patients who present with clinically stage III disease. For patients with stage II disease who achieve a pathological complete response, the available evidence suggests that their predicted local regional recurrence risk without regional or postmastectomy radiation is 10% or less. Therefore the benefit from radiation is likely low and it is reasonable weigh out these small potential benefits in the context of associated treatment morbidities and costs. It is also important to further consider additional local-regional risk factors such as patient age, tumor biology, plans for prolonged systemic therapies, and other pathological factors at presentation in making radiation treatment decisions for such patients. Citation Format: Buchholz T. Indications for radiation treatments after neoadjuvant chemotherapy while awaiting the results of clinical trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES7-3.

Abstract P1-11-13: Depomedroxyprogesterone therapy for hot flashes in survivors of ER-expressing breast cancer: Impact on recurrence and survival

Abstract Background Survivors of ER-expressing operable breast cancer (ER+BC) generally do not receive hormone replacement therapy for menopausal symptoms due to concern about provoking recurrence of disease. Single dose depomedroxyprogesterone acetate (MPA) 400 mg IM has previously been shown (Loprinzi CL, et al. J Clin Oncol 2006;24:1409) to be the most effective non-estrogen therapy available for menopausal hot flashes (HF) but long-term evidence of safety in survivors of ER+BC is lacking. Methods Consecutive patients previously diagnosed with ER+BC who received MPA for HF between January 2007 and December 2012 were retrospectively identified in the breast cancer patient database at Mayo Clinic Arizona. Medical records were audited for breast cancer outcomes in these cases and in contemporaneous control patients with ER+BC who did not receive MPA, matched for age, stage of disease, and year of diagnosis. Statistical comparisons of local-regional recurrence and event-free survival were performed. Results 92 patients who received MPA were identified and matched 1:1 with contemporaneous controls. Median follow-up duration was 5.7 years in cases and 4.5 years in controls. Estimated local-regional recurrence free survival at 10 years was 85% (95% CI, 72-100%) in cases and 95% (95% CI, 86-100%) in controls. Matched pairs hazard ratio was 1.0 (95% CI, 0.06-16.0) for local-regional recurrence free survival. Estimated event-free survival at 10 years was 81% (95% CI, 69-97%) in cases and 76% (95% CI, 64-92%) in controls. Matched pairs hazard ratio was 0.38 (95% CI, 0.10-1.41) for event-free survival. The majority (77%) of case patients experienced satisfactory relief of hot flashes from MPA injection. Conclusion In this retrospective case-control study we were unable to identify a detrimental effect of MPA therapy for HF in survivors of ER+BC. MPA may be acceptable for management of HF in this population. Citation Format: Ertz-Archambault N, Rogoff L, Kosiorek H, Ernst B, Anderson K, Pockaj B, Gray R, Northfelt D. Depomedroxyprogesterone therapy for hot flashes in survivors of ER-expressing breast cancer: Impact on recurrence and survival [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-13.

Strategies of surgical and comprehensive management of breast cancer patients with local regional recurrence

Breast conserving surgery and sentinel lymph node biopsy are widely used in early breast cancer treatment. Right now, the mode of local regional recurrence (LRR) has significantly changed and the rate of ipsilateral breast tumor recurrence and axillary lymph node recurrence are steadily increasing. Due to its relatively low incidence of LRR compared with distant metastasis, inconsistent of pre-recurrence treatment, difficulty in surgical treatment, and few prospective clinical studies, there are rising new challenges for clinical management of LRR patients. In this article, based on new theory of LRR, clinical diagnosis and treatment progress, and our own clinical practice experience for LRR breast cancer patients, we propose that we should make pathological diagnosis and do systemic evaluation for LRR disease, then considering it as a curable disease, and integrating local and systemic comprehensive treatment for LRR patients, thus to improve their disease outcome.