[Show abstract][Hide abstract] ABSTRACT: Purpose:
The role of postmastectomy radiotherapy (PMRT) in clinically node-positive, stage II-III breast cancer patients with pathological negative nodes (ypN0) after neoadjuvant chemotherapy (NAC) remains controversial.
A total of 1560 clinically node-positive, stage II-III breast cancer patients treated with NAC and mastectomy who achieved ypN0 between 1998 and 2009 in the National Cancer Database were analyzed. The effects of PMRT on overall survival (OS) for the entire cohort and multiple subgroups were evaluated. Imputation and propensity score matching were used as sensitivity analyses to minimize biases.
Of the entire 1560 eligible patients, 903 (57.9%) received PMRT and 657 (42.1%) didn't. At a median follow-up of 56.0 months, no statistical difference was observed for OS between two groups by univariate and multivariate analyses (P = 0.120; HR 1.571, 95% CI 0.839-2.943). On subgroup analyses, PMRT significantly improved OS in patients with clinical stage IIIB/IIIC disease, T3/T4 tumor, or residual invasive breast cancer after NAC (P < 0.05). This improvement in OS remained significant after sensitivity analyses for the propensity score-matched patients.
This study demonstrated that PMRT showed a heterogeneous effect in clinically node-positive, stage II-III breast cancer patients with ypN0 following NAC. PMRT improved OS for patients with clinical stage IIIB/IIIC disease, T3/T4 tumor, or residual invasive breast tumor after NAC. In the absence of definitive conclusions from prospective studies, including the ongoing NSABP B-51 trial, our findings may help identify specific groups of women with clinically node-positive, stage II-III breast cancers who could benefit from PMRT after NAC.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We aimed to assess the effect of age on survival according to estrogen receptor (ER) and progesterone receptor (PR)-defined lobular breast cancer subtype in a wide age range.
43,230 invasive lobular breast cancer women without comorbidities diagnosed between 2004 and 2011 in the National Cancer Database (NCDB) were analyzed. The effects of age on overall survival (OS) among different age groups were evaluated by log-rank test and Cox proportional model.
Multivariate analysis showed that patients diagnosed at both young (<35 years) and old (≥70 years) ages had worse prognosis compared with those in the middle ages. We further analyzed the interaction between age and molecular subtype for predicting OS: in ER+PR+ subtype, the HR of OS declined with age from 1.55 (95% CI, 1.08-2.22; P = 0.019) in the group younger than 35 years to 1.38 (1.02-1.86; P = 0.036) in the 35-39 group, but increased with age to 10.1 (8.49-11.94; P < 0.001) in the group older than 79. While in ER+PR- and ER-PR- subtypes, the HRs showed no statistical differences among women diagnosed before 60 (P > 0.1); and in ER-PR+ subgroup, the HRs were similar in patients younger than 70 (P > 0.1); thus, the plots of HRs in these three subtypes remained steady until the age of 60 or 70.
Our findings identified that the effect of age on OS in lobular breast cancer varied with ER/PR-defined subtypes. Personalized treatment strategies should be developed to improve outcomes of breast cancer patients with different ages and ER/PR statuses.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Recent studies have revealed that breast-conserving surgery (BCS) with radiotherapy (RT) led to better survival than mastectomy in some populations. We compared the efficacy of BCS+RT and mastectomy using the National Cancer Database (NCDB, USA).
Non-metastatic breast cancers in the NCDB from 2004-2011 were identified.The Kaplan-Meier method, Coxregression and propensity score analysis were used to compare the overall survival (OS) among patients with BCS+RT, mastectomy alone and mastectomy+RT.
A total of 160,880 patients with a median follow-up of 43.4 months were included. The respective 8-year OS values were 86.5%, 72.3% and 70.4% in the BCS+RT, mastectomy alone and mastectomy+RT group, respectively (P < 0.001). After exclusion of patients with comorbidities, mastectomy (alone or with RT) remained associated with a lower OS in N0 and N1 patients. However, the OS of mastectomy+RT was equivalent to BCS+RT in N2-3 patients. Among patients aged 50 or younger, the OS benefit of BCS+RT over mastectomy alone was statistically significant (HR1.42, 95% CI 1.16-1.74), but not clinically significant (<5%) in N0 patients, whereas in N2-3 patients, the OS of BCS+RT was equivalent to mastectomy+RT (85.2% vs. 84.8%). The results of the propensity analysis were similar.
BCS+RT resulted in improved OS compared with mastectomy ± RT in N0 and N1 patients. In N2-3 patients, BCS+RT has an OS similar to mastectomy+RT when patients with comorbidities were excluded. Among patients aged 50 or younger, the OS of BCS+RT is equivalent to mastectomy ± RT.
[Show abstract][Hide abstract] ABSTRACT: Lymph node metastasis is a major prognostic factor for perihilar cholangiocarcinoma (PHC). However, prognostic significance of extent of node dissection, lymph node ratio (LNR), number and location of positive nodes remain unclear. We aimed to evaluate whether node status, LNR, number or location of positive nodes are independent factors for staging in PHC, and to determine the minimum requirements for node examination.
The Surveillance, Epidemiology, and End Results database was used to identify 1,116 resected PHCs from 1998 to 2008. The correlation between nodal status and survival was analyzed retrospectively.
Lymph node metastasis occurred in 43.4% patients and was an independent predictor for overall survival (OS) and cancer-specific survival (CSS). No survival benefit was observed for an increasing number of node retrieval in node-positive patients. However, in node-negative patients, ≥13 node dissection was of more survival benefit than 3 ≤ total lymph node count (TLNC) ≤ 12 and TLNC < 3 (5-year OS: 52.8% vs. 39.7% vs. 26.3%, P = 0.001; 5-year CSS: 60.6% vs. 46.3% vs. 30.0%, P = 0.001). No difference in survival between patients with regional and distant node involvement was found. Survival for patients with >3 positive nodes was significantly worse than that for those with 3 or less (RR: 1.466, P = 0.001). And patients with LNR > 0.27 also had unfavorable prognosis (RR: 1.376:, P = 0.001).
To adequately assess nodal status of this life-threatening disease, 13 or more nodes retrieval should be considered. Number of positive nodes and LNR rather than location of metastatic nodes may be defined as parameters for staging of PHC.
This article is protected by copyright. All rights reserved.
No preview · Article · Aug 2015 · Journal of Gastroenterology and Hepatology
[Show abstract][Hide abstract] ABSTRACT: A multicenter, prospective, blinded study was performed to test the feasibility of using a handheld optical imaging probe for the intraoperative assessment of final surgical margins during breast-conserving surgery (BCS) and to determine the potential impact on patient outcomes.
Forty-six patients with early-stage breast cancer (one with bilateral disease) undergoing BCS at two study sites, the Johns Hopkins Hospital and Anne Arundel Medical Center, were enrolled in this study. During BCS, cavity-shaved margins were obtained and the final margins were examined ex vivo in the operating room with a probe incorporating optical coherence tomography (OCT) hardware and interferometric synthetic aperture microscopy (ISAM) image processing. Images were interpreted after BCS by three physicians blinded to final pathology-reported margin status. Individual and combined interpretations were assessed. Results were compared to conventional postoperative histopathology.
A total of 2,191 images were collected and interpreted from 229 shave margin specimens. Of the eight patients (17 %) with positive margins (0 mm), which included invasive and in situ diseases, the device identified all positive margins in five (63 %) of them; reoperation could potentially have been avoided in these patients. Among patients with pathologically negative margins (>0 mm), an estimated mean additional tissue volume of 10.7 ml (approximately 1 % of overall breast volume) would have been unnecessarily removed due to false positives.
Intraoperative optical imaging of specimen margins with a handheld probe potentially eliminates the majority of reoperations.
No preview · Article · Jul 2015 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Preoperative sentinel node localization (SNL) using a subareolar injection of radiotracer technetium-99m-sulfur colloid (Tc(99m)SC) is associated with significant pain. Lidocaine use during SNL is not widely adopted partly due to a concern that it can obscure sentinel node identification and reduce its diagnostic accuracy. We prospectively identified women with a biopsy-proven infiltrating breast cancer who were awaiting a SNL. The women completed the McGill pain questionnaire, Visual Analog Scale, and Wong-Baker FACES Pain Rating Scale prior to and following SNL. We identified a retrospective cohort of women with similar demographic and tumor characteristics who did not receive lidocaine before SNL. We compared sentinel lymph node identification rates in the two cohorts. We used Wilcoxon rank sum tests to compare continuous measures and Fisher's exact test for categorical measures. Between January 2011 to July 2012, 110 women consented, and 105 were eligible for and received lidocaine prior to Tc(99m)SC injection. The post-lidocaine identification rate of SNL was 95 % with Tc(99m)SC, and 100 % with the addition of intraoperative methylene blue dye/saline. Pain range prior to and following the SNL was unchanged (P = 0.703). We identified 187 women from 2005 to 2009 who did not receive lidocaine during preoperative SNL. There was no significant difference in the success rate of SNL, with or without lidocaine (P = 0.194). The administration of lidocaine during SNL prevents pain related to isotope injection while maintaining the success rate. We have changed our practice at our center to incorporate the use of lidocaine during all SNL.
No preview · Article · Mar 2015 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen are known to have an elevated risk of subsequent endometrial cancer. However, it is unclear if ER-negative patients also have a higher risk of endometrial cancer. This population-based study aims to evaluate whether breast cancer patients with distinctive ER and PR status possess differential risks in developing delayed endometrial malignancy. Data were obtained from the Surveillance, Epidemiology, and End Results program (1992-2009). Standardized incidence ratio (SIR) was calculated as the observed cases of endometrial cancers among breast cancer survivors compared with the expected cases in the general population. Data were stratified by latency periods, race, age, and calendar year of breast cancer diagnosis. We identified 2044 patients who developed a second primary endometrial cancer among 289,933 breast cancer survivors. The overall SIRs for subsequent endometrial cancers were increased in all of the four subtypes (ER+PR+, ER+PR-, ER-PR+, and ER-PR-) of breast cancer. SIR was increased for all latency periods except for the initial 6-11 months after breast cancer diagnosis. Stratifying by age of diagnosis, elevated SIRs in all ER/PR groups were statistically significant among patients diagnosed with breast cancer after the age of 40. Demographically, non-Hispanic whites had increased SIRs in all subtypes of breast cancer, while Hispanic whites had no statistically elevated SIRs. Here we showed that patients with invasive breast cancer have a higher risk of developing subsequent endometrial cancer regardless of ER or PR status. The increased risk among hormone receptor-negative breast cancer survivors raises concerns whether common etiological factors among these breast cancer subtypes increase the susceptibility to develop endometrial cancer. Lower threshold for routine endometrial cancer surveillance may be warranted.
Full-text · Article · Mar 2015 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy (RT) may be omitted for elderly (age >70 years) breast cancer patients with favorable disease [stage I and estrogen receptor (ER)-positive with endocrine therapy]. This study sought to develop a nomogram to predict the survival benefit of RT in elderly patients with stage I & ER-negative or stage II/III (regardless of ER status) disease.
We used surveillance, epidemiology and end results data to identify 9,079 patients (age ≥70 years) with stage I & ER-negative or stage II/III (regardless of ER status) disease who received breast-conserving surgery between 1990 and 2005. Cancer-specific survival (CSS) was estimated using Kaplan-Meier analysis. Competing-risk regression was used to determine the effect of predictors on CSS. A nomogram was then developed and validated using bootstrapped technique.
With a median follow-up of 83 months, the overall 10- and 15-year CSS were 82.1 and 75.8 %, respectively. RT was significantly associated with improved CSS in the multivariate analysis. A nomogram was developed for the prediction of 10-year CSS and showed a bootstrapped-corrected area under the curve value of 0.679. RT did not deliver any survival benefit to patients with predicted CSS >90 %. In addition, RT significantly increased the 10-year CSS by 3.6 and 10.1 % in patients with predicted CSS from 0.80 to 0.90 and <0.80, respectively.
This nomogram is a useful tool to predict the 10-year CSS in patients with stage I and ER-negative or stage II/III (regardless of ER status) disease. The benefit of RT varied among patients with different predicted CSS.
Preview · Article · Feb 2015 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Detecting circulating plasma tumor DNA (ptDNA) in early stage cancer patients has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection.
In this prospective study, primary breast tumors and matched pre- and post-surgery blood samples were collected from early stage breast cancer patients (n=29). Tumors (n=30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR.
Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Pre-surgery plasma samples (n=29) were then analyzed for PIK3CA mutations using ddPCR. Of the fifteen PIK3CA mutations detected in tumors by ddPCR, fourteen of the corresponding mutations were detected in pre-surgical ptDNA, while no mutations were found in plasma from patients with PIK3CA wild type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation positive ptDNA pre-surgery had ddPCR analysis of post-surgery plasma, with five patients having detectable ptDNA post-surgery.
This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in early stage breast cancer patients. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.
No preview · Article · Feb 2014 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
Preoperative sentinel node localization (SNL) is now a standard of care for patients undergoing surgical treatment for breast cancer. It requires a subareolar injection of radiotracer Tc99-sulfur colloid which often causes severe pain for a few minutes (if lidocaine is not used), but has been characterized by numerous patients as the “worst pain of my life.” Subareolar administration of lidocaine in conjunction with the radiotracer injection has been demonstrated to be effective in alleviating pain during SNL. However, the use of lidocaine during SNL is not a widely adopted practice. One concern is that lidocaine use can obscure the subsequent identification of sentinel node during surgery and thereby reduce the diagnostic accuracy of SNL. This project aims to compare the diagnostic accuracy of SNL with and without lidocaine injection prior to the injection of Tc99-sulfur colloid utilizing ultrasound guidance. We hypothesize that lidocaine administration will not impact accurate identification of the axillary sentinel lymph node.
This study is IRB approved and HIPAA compliant. For the pre-intervention phase, we performed a retrospective analysis of surgical rates of sentinel lymph node identification from 205 women from 2005-2009 who did not receive lidocaine during preoperative SNL. For the post-intervention phase, women were enrolled from January 2011 to July 2012 and surgical identification rates were analyzed. Both groups were identified from the Johns Hopkins Breast Center and the same eligibility criteria were used. Exclusion criteria include painful cancer, lidocaine allergy, age younger than 18, lesion or microcalcifications >4cm in the upper outer breast, prior surgical interventions in upper outer breast, and history of chemotherapy and tamoxifen treatment. All of the exclusions were for the possibility of impeding lymphatic drainage to the axilla for reasons other than the additional injection of lidocaine. Patients who consented to the prospective portion were interviewed and given the McGill pain questionnaire to complete prior to and after the SNL. The diagnostic accuracy of SNL was determined by successful identification of the sentinel node during surgery based on medical record review, for both pre- and post-intervention groups. We evaluated the proportion of women with successful SNL by technetium alone and those requiring additional periareolar intraoperative injection of methylene blue dye or saline to assist in the sentinel node identification. To assess the similarity between the pre- and post intervention groups, demographic and tumor characteristics of both groups were collected and compared, including age, ethnicity, tumor type, size, grade, estrogen receptor/progesterone receptor/HER2 positivity, and status of nodal metastasis. P values for differences between cohorts are from Wilcoxon rank sum tests comparing continuous measures and Fisher's exact test for categorical measures.
The pre- and post-intervention groups have similar demographic and tumor characteristics. In the pre- intervention group, 204 patients were included; the diagnostic accuracy of SNL is 94% and 100% with the use of intraoperative methylene blue dye/saline (table). In the post-intervention group, 107 patients (80% participation rate) consented to and received the lidocaine administration prior to the radiotracer injection. The post-lidocaine diagnostic accuracy of SNL is 95% and 100% with the use of intraoperative methylene blue dye/saline (table). There is no significant difference in diagnostic accuracy of SNL pre- and post- lidocaine intervention. The reported level of pain following lidocaine injection is very low (mean = 0.481) on the McGill pain scale of 0 to 10.
The administration of lidocaine during preoperative SNL not only reduces patient pain but also maintains diagnostic accuracy of the procedure itself. Our project validates a patient-centered approach for performing a standard-of-care procedure in breast cancer treatment. At our institution, because of the encouraging result of this project, we have changed our practice behavior to incorporate the use of lidocaine during all preoperative sentinel lymph node injections (unless there is a lidocaine allergy).
[Show abstract][Hide abstract] ABSTRACT: Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood. Using this technique, we identified mutant PIK3CA DNA in circulating ptDNA (plasma tumor DNA) from a patient with concurrent early stage breast cancer and non-small cell lung cancer. The patient underwent successful resection of both her breast and lung cancers, and using standard Sanger sequencing the breast cancer was shown to harbor the identical PIK3CA mutation identified in peripheral blood. This case report highlights potential applications and concerns that can arise with the use of ptDNA in clinical oncology practice.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not.
Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples.
Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed.
Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.
No preview · Article · May 2013 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Collagen I (Col1) fibers are a major structural component in the extracellular matrix of human breast cancers. In a preliminary pilot study, we explored the link between Col1 fiber density in primary human breast cancers and the occurrence of lymph node metastasis. Col1 fibers were detected by second harmonic generation (SHG) microscopy in primary human breast cancers from patients presenting with lymph node metastasis (LN+) versus those without lymph node metastasis (LN-). Col1 fiber density, which was quantified using our in-house SHG image analysis software, was significantly higher in the primary human breast cancers of LN+ (fiber volume=29.22%±4.72%, inter-fiber distance=2.25±0.45 μm) versus LN- (fiber volume=20.33%±5.56%, inter-fiber distance=2.88±1.07 μm) patients. Texture analysis by evaluating the co-occurrence matrix and the Fourier transform of the Col1 fibers proved to be significantly different for the parameters of co-relation and energy, as well as aspect ratio and eccentricity, for LN+ versus LN- cases. We also demonstrated that tissue fixation and paraffin embedding had negligible effect on SHG Col1 fiber detection and quantification. High Col1 fiber density in primary breast tumors is associated with breast cancer metastasis and may serve as an imaging biomarker of metastasis.
No preview · Article · Nov 2012 · Journal of Biomedical Optics
[Show abstract][Hide abstract] ABSTRACT: The indications of neoadjuvant chemotherapy for breast cancer are extending to a larger population of breast cancer patients. The aims of this therapy are to transform the cancer to an operable form, downsize the tumor volume to allow a lumpectomy instead of a mastectomy, or to perform an in vivo test of the effect of the treatment on breast cancer in a specific individual. Along with these benefits, there is concern about the safety of lumpectomy and sentinel lymph node biopsy after neoadjuvant chemotherapy. In this review, we discuss the experience of breast conservation therapy after neoadjuvant chemotherapy and the reported recurrence rates in the preserved breasts. An overview of the studies that utilized sentinel lymph node biopsy after neoadjuvant chemotherapy is presented, summarizing the identification rates and false-negative rate.
No preview · Article · Dec 2011 · Current Breast Cancer Reports