Jee Ye Kim

Does Liver Resection Provide Long-Term Survival Benefits for Breast Cancer Patients with Liver Metastasis? A Single Hospital Experience

Purpose Liver resection with colorectal liver metastasis widely accepted and has been considered safe and effective therapeutic option. However, the role of liver resection in breast cancer with liver metastasis is still controversial. Therefore, we reviewed the outcome of liver resection in breast cancer patients with liver metastases in a single hospital experiences. Materials and Methods Between January 1991 and December 2006, 2176 patients underwent breast cancer surgery in Gangnam Severance Hospital. Among these patients, 110 cases of liver metastases were observed during follow-up and 13 of these patients received liver resection with potential feasibility to achieve an R0 resection. Results The median time interval between initial breast cancer and detection of liver metastasis was 62.5 months (range, 13-121 months). The 1-year and 3-year overall survival rates of the 13 patients with liver resection were 83.1% and 49.2%, respectively. The 1-year and 3-year overall survival rates of patients without extrahepatic metastasis were 83.3% and 66.7% and those of patients with extrahepatic metastasis were 80.0% and 0.0%, respectively (p=0.001). Conclusion Liver resection for metastatic breast cancer results in improved patient survival, particularly in patients with solitary liver metastasis and good general condition.

Prognostic Nomogram for Prediction of Axillary Pathologic Complete Response After Neoadjuvant Chemotherapy in Cytologically Proven Node-Positive Breast Cancer.

AbstractTo develop a nomogram predicting probability of axillary pathologic complete response (pCR) in patients with cytologically proven axillary node-positive breast cancer who received neoadjuvant chemotherapy (NAC).The current management of axillary intervention in node-positive breast cancer patients who received NAC is axillary lymph node dissection (ALND) regardless of axillary pCR.We reviewed the records of 415 patients with cytologically proven node-positive breast cancer that were treated with NAC followed by surgery between 2008 and 2012 at Severance Hospital, Yonsei University Health System. Baseline patient and tumor characteristics, chemotherapy regimen, and tumor and nodal responses were analyzed. A nomogram was developed using a binary logistic regression model with a training cohort and validated in an independent cohort of 110 patients.Axillary pCR was achieved in 38.8% of the patients who underwent ALND after NAC. Axillary pCR was associated with initial clinical nodal status, negative estrogen receptor status, positive human epidermal growth factor receptor 2 (HER2) status with trastuzumab, and clinical nodal and tumor responses. A nomogram was developed based on the clinical and statistically significant predictors. It had good discrimination performance (AUC 0.82, 95% CI, 0.78–0.86) and calibration fit. The nomogram was independently validated, indicating the good predictive power of the model (AUC 0.80, 95% CI, 0.72–0.88).Our nomogram might help predict axillary pCR after NAC in patients with initially node-positive breast cancer. Patients with a high probability of achieving axillary pCR could be spared ALND, avoiding postoperative morbidity.

Comparisons of Oncologic Outcomes between Triple-Negative Breast Cancer (TNBC) and Non-TNBC among Patients Treated with Breast-Conserving Therapy.

Purpose The optimum local surgical strategy regarding breast-conserving therapy (BCT) for triple-negative breast cancer (TNBC) is controversial. To investigate whether BCT is appropriate for patients with TNBC, we evaluated the clinical outcomes of BCT in women with TNBC compared to those of women without TNBC, using a large, single-center cohort. Materials and Methods We performed a retrospective analysis of 1533 women (TNBC n=321; non-TNBC n=1212) who underwent BCT for primary breast cancer between 2000 and 2010. Clinicopathological characteristics, locoregional recurrence-free survival (LRFS), and overall survival (OS) were analyzed. Results Tumors from the TNBC group had a higher T stage (T2 37.4% vs. 21.0%, p<0.001), a lower N stage (N0 86.9% vs. 75.5%, p<0.001), and a higher histologic grade (Grade III 66.8% vs. 15.4%, p<0.001) than the non-TNBC group. There were no differences in 5-year LRFS rates between the TNBC and non-TNBC groups (98.7% vs. 97.8%, p=0.63). The non-TNBC group showed a slightly better 5-year OS than the TNBC group; however, the difference was not significant (96.2% vs. 97.3%, p=0.72). In multivariate analyses, TNBC was not associated with poor clinical outcomes in terms of LRFS and OS [hazard ratio (HR) for LRFS=0.37, 95% confidence interval (CI): 0.10–1.31; HR for OS=1.03, 95% CI: 0.31–3.39]. Conclusion TNBC patients who underwent BCT showed non-inferior locoregional recurrence compared to non-TNBC patients with BCT. Thus, BCT is an acceptable surgical approach in patients with TNBC.

Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women

AbstractCurrently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes.We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance.Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2-negative subtype in postmenopausal but not premenopausal patients.Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer.

Preoperative Magnetic Resonance Imaging and Survival Outcomes in T1–2 Breast Cancer Patients Who Receive Breast-Conserving Therapy

Purpose The purpose of the study was to evaluate the effect of preoperative magnetic resonance imaging (MRI) on survival outcomes for breast cancer. Methods A total of 954 patients who had T1–2 breast cancer and received breast-conserving therapy (BCT) between 2007 and 2010 were enrolled. We divided the patients according to whether they received preoperative MRI or not. Survival outcomes, including locoregional recurrence-free survival (LRRFS), recurrence-free survival (RFS), and overall survival (OS), were analyzed. Results Preoperative MRI was performed in 743 of 954 patients. Clinicopathological features were not significantly different between patients with and without preoperative MRI. In the univariate analyses, larger tumors were marginally associated with poor LRRFS compared to smaller tumors (hazard ratio [HR], 3.22; p=0.053). Tumor size, histologic grade, estrogen receptor (ER), progesterone receptor (PR), hormonal therapy, and adjuvant chemotherapy status were associated with RFS. Larger tumor size, higher histologic grade, lack of ER and PR expression, and no hormonal therapy were associated with decreased OS. Tumor size was associated with LRRFS in the multivariate analyses (HR, 4.19; p=0.048). However, preoperative MRI was not significantly associated with LRRFS, RFS, or OS in either univariate or multivariate analyses. Conclusion Preoperative MRI did not influence survival outcomes in T1–2 breast cancer patients who underwent BCT. Routine use of preoperative MRI in T1–2 breast cancer may not translate into longer RFS and OS.

Next-generation sequencing of BRCA1/2 in breast cancer patients: potential effects on clinical decision-making using rapid, high-accuracy genetic results

Purpose We evaluated the clinical role of rapid next-generation sequencing (NGS) for identifying BRCA1/2 mutations compared to traditional Sanger sequencing. Methods Twenty-four paired samples from 12 patients were analyzed in this prospective study to compare the performance of NGS to the Sanger method. Both NGS and Sanger sequencing were performed in 2 different laboratories using blood samples from patients with breast cancer. We then analyzed the accuracy of NGS in terms of variant calling and determining concordance rates of BRCA1/2 mutation detection. Results The overall concordance rate of BRCA1/2 mutation identification was 100%. Variants of unknown significance (VUS) were reported in two cases of BRCA1 and 3 cases of BRCA2 after Sanger sequencing, whereas NGS reported only 1 case of BRCA1 VUS, likely due to differences in reference databases used for mutation identification. The median turnaround time of Sanger sequencing was 22 days (range, 14–26 days), while the median time of NGS was only 6 days (range, 3–21 days). Conclusion NGS yielded comparably accurate results to Sanger sequencing and in a much shorter time with respect to BRCA1/2 mutation identification. The shorter turnaround time and higher accuracy of NGS may help clinicians make more timely and informed decisions regarding surgery or neoadjuvant chemotherapy in patients with breast cancer.

Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers

Purpose The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values. Patients and Methods Ki-67 levels were immunohistochemically measured using paired biopsy and surgical specimens in 310 breast cancer patients between 2008 and 2013. ΔKi-67 was calculated by postoperative Ki-67 minus preoperative levels. The outliers of ΔKi-67 were defined as [lower quartile of ΔKi-67–1.5 × interquartile range (IQR)] or (upper quartile + 1.5 × IQR) and were evaluated according to clinicopathological parameters by logistic regression analysis. Results The median preoperative and postoperative Ki-67 levels were 10 (IQR, 15) and 10 (IQR, 25), respectively. Correlation of Ki-67 levels between the two specimens indicated a moderately positive relationship (coefficient = 0.676). Of 310 patients, 44 (14.2%) showed outliers of ΔKi-67 (range, ≤-20 or ≥28). A significant association with poor prognostic factors was found among these patients. Multivariate analysis determined that significant risk factors for outliers of ΔKi-67 were tumor size >1 cm, negative progesterone receptor (PR) expression, grade III cancer, and age ≤35 years. Among 171 patients with luminal human epidermal growth factor receptor 2-negative tumors, breast cancer subtype according to preoperative or postoperative Ki-67 levels discordantly changed in 46 (26.9%) patients and a significant proportion of patients with discordant cases had ≥1 risk factor. Conclusion Ki-67 expression showed a substantial concordance between biopsy and surgical specimens. Extremely discordant Ki-67 levels may be associated with aggressive tumor biology. In patients with luminal subtype disease, clinical application of Ki-67 values should be cautious considering types of specimens and clinicopathological risk factors.

Prognostic Tests for Estrogen Receptor-Positive Breast Cancer: Need for Global Consideration and Further Evolution.

The NSABP B-31 trial testing the efficacy of adjuvant trastuzumab was almost derailed right after launching because 18% of the enrolled patients were found to be ERBB2-negative (formerly HER2 or HER2/neu) on central review of the initial 104 patients.1 This prompted international efforts to improve reliability of ERBB2 testing, eventually leading to American Society of Clinical Oncology/ College of American Pathologists Guideline for HER2 Testing. Ironically, OncotypeDx owes its creation to this event. While the NSABP B-20 trial has demonstrated a clear benefit from chemotherapy added to tamoxifen for patients diagnosed as having estrogen receptor–positive breast cancer that did not metastasize to axillary lymph nodes (ER+/N− BC), a 10year distant disease-free survival rate of 85% for tamoxifentreated patients suggested that there would be a clinically significant overtreatment if all patients with ER+/N− BC were treated with chemotherapy. However, the dogma of “proportional hazard reduction” dictated that chemotherapy effect would be independent of prognosis. This resulted in the National Comprehensive Cancer Network (NCCN) and St Gallen clinical practice guidelines of categorizing less than 10% of patients with ER+/N− BC as being at low enough risk that they do not require chemotherapy. Although DNA flow cytometry and Ki67 were proposed as potential predictive markers, they simply were not reproducible enough to be considered for clinical development. A HER2 testing fiasco that surfaced while the NSABP B-31 was conducted simply furthered the exclusion of these biomarkers from consideration. By the end of the last millennium, clinical oncologists had lost confidence in traditional histopathologyor immunohistochemistry-based biomarkers based on bad experience with ERBB2.2 OncotypeDx was developed with a clear intent to address this conundrum. Two studies using archived tumor blocks from NSABP B-143 and B-204 demonstrated that OncotypeDx classified more than 50% of patients with ER+/N− BC into a lowrisk group that did not benefit from chemotherapy, in contrast to only 10% by using clinical guidelines. Successful development of OncotypeDx demonstrated 2 important facts: (1) the dogma of proportional hazard reduction no longer could be applied to ER+/N− BC, in that only a subset of those patients benefit from chemotherapy, and (2) a reproducible clinical assay can be developed using degraded total RNA extracted from old archived formalin-fixed, paraffinembedded tumor blocks (FFPET). Suddenly, molecular profiling was no longer a domain of laboratory scientists but became an important tool for clinical oncologists. Since the publication of OncotypeDx results, many gene expression–based prognostic tests for FFPET have appeared, and all looked remarkable in their performance as prognostic tests for ER+/N− BC. Genomic grade examined in the BIG-1-98 trial, reported in this issue by Ignatiadis et al,5 was one of them. Many investigators have wondered why all these tests performed so well when there was a remarkable lack of overlap of gene lists among them. Meta-analysis of BC microarray gene expression profiling data conducted by Wirapati et al6 provided a biological answer to this question: they are all a surrogates of proliferation. The key summary finding from this remarkable report6 was that all published gene expression profiling–based prognostic tests essentially identified ER+ BC with low proliferation (ie, luminal A instrinsic subtype) as low risk, whereas ER− tumors with intrinsically high proliferation rates are mostly classified as high risk, together with ER+ BC with a high proliferation rate (ie, luminal B subtype). Thus, this meta-analysis6 suggests that any gene expression–based prognostic tests can identify patients who do not need chemotherapy among those with ER+/N− BC. Unfortunately, this is not the case in reality. What the meta-analysis6 showed was that when the same technical platform was used to measure gene expression, the gene list and algorithm used by these tests identify the same tumors as low risk. That does not mean that the actual clinical tests perform the same, because their actual performances are subject to idiosyncrasies imposed by technical platforms, probe or primer design, and data normalization and standardization methods.7 In fact, studies8 have demonstrated only moderate concordance between OncotypeDx and other gene expression–based tests. For example, there was only 76% concordance between OncotypeDx and EndoPredict.9 This level of concordance is not too different from concordance levels between OncotypeDxand Ki67-based risk algorithms.10 The fact that physical evidence of clinical utility as a predictive maker for chemotherapy benefit exists only for OncotypeDx4 poses a significant dilemma for those involved in developing clinical guidelines. In fact, OncotypeDx remains the only predictive test identified in the NCCN guideline as of 2015. Regrettably, archived tumor blocks from NSABP B-20 cannot be used for validation of these other promising tests because the blocks have been nearly depleted and are also very old (a sigRelated article Opinion

Impact of Micrometastatic Axillary Nodes on Survival of Breast Cancer Patients with Tumors ≤2 cm

AbstractBackgroundThis study investigated the impact of pN1mi disease on the survival of T1 breast cancer patients and examined the clinical usefulness of the online PREDICT tool and updated staging system. MethodsThe node stages of 2344 patients were divided into pN0, pN1mi, and pN1a. Clinicopathological parameters and survival outcomes were retrospectively analyzed. Data for 111 micrometastatic diseases were applied to the PREDICT version 2.0 and re-classified using the 8th edition of the cancer staging manual.ResultsUnivariable analyses demonstrated worse disease-free and overall survival rates for patients with node-positive cancer; however, the significance was not maintained in multivariable analyses. Chemotherapy improved outcomes in patients with node-positive and non-luminal A-like subtype cancers. The PREDICT tool demonstrated good performance when estimating the 5-year overall survival for pN1mi disease (area under the receiver operating characteristic curve, 0.834). According to the updated staging system, 74% of cases were down-staged to IA, and clearly splitting survival curves were identified.ConclusionpN1mi disease alone did not adversely affect survival outcomes. Biologic and treatment factors determined outcomes in cases of small-volume node micrometastasis. The PREDICT tool or new staging classification could help predict the survival of patients with micrometastatic sentinel nodes.

External validation of IBTR! 2.0 nomogram for prediction of ipsilateral breast tumor recurrence

Purpose IBTR! 2.0 nomogram is web-based nomogram that predicts ipsilateral breast tumor recurrence (IBTR). We aimed to validate the IBTR! 2.0 using an external data set. Materials and Methods The cohort consisted of 2,206 patients, who received breast conserving surgery and radiation therapy from 1992 to 2012 at our institution, where wide surgical excision is been routinely performed. Discrimination and calibration were used for assessing model performance. Patients with predicted 10-year IBTR risk based on an IBTR! 2.0 nomogram score of <3%, 3%–5%, 5%–10%, and >10% were assigned to groups 1, 2, 3, and 4, respectively. We also plotted calibration values to observe the actual IBTR rate against the nomogram-derived 10-year IBTR probabilities. Results The median follow-up period was 73 months (range, 6 to 277 months). The area under the receiver operating characteristic curve was 0.607, showing poor accordance between the estimated and observed recurrence rate. Calibration plot confirmed that the IBTR! 2.0 nomogram predicted the 10-year IBTR risk higher than the observed IBTR rates in all groups. High discrepancies between nomogram IBTR predictions and observed IBTR rates were observed in overall risk groups. Compared with the original development dataset, our patients had fewer high grade tumors, less margin positivity, and less lymphovascular invasion, and more use of modern systemic therapies. conclusions IBTR! 2.0 nomogram seems to have the moderate discriminative ability with a tendency to over-estimating risk rate. Continued efforts are needed to ensure external applicability of published nomograms by validating the program using an external patient population.