Surveillance for Distant Metastasis in Breast Cancer Patients Who Underwent Contemporary Management: A Report from the Korean Breast Cancer Society Survivor Research Group.

BACKGROUND: Current guidelines recommend against the use of routine imaging tests to detect distant metastasis in asymptomatic breast cancer patients. However, recent advancements in effective therapeutics and diagnostic accuracy have raised the need to reassess the clinical efficacy of intensive metastasis surveillance. We report the results of a multicenter retrospective study to investigate the association between intensive imaging studies and survival outcomes. PATIENTS AND METHODS: We retrospectively reviewed the data of 4130 patients who underwent surgery from 11 hospitals in Korea between January 2010 and December 2011. Patients were divided into two groups on the basis of the intensity of metastasis imaging studies during their disease-free period. The types and intervals of the imaging studies were based on each physician's decisions. RESULTS: High-intensive screening showed a shorter distant metastasis-free survival [p < 0.001, hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.29-2.04], especially for patients in whom bone or lung was the first site of metastasis. With a median follow-up period of 110.0 months, the 5-year breast cancer-specific survival (BCSS) rate was 96.5%. The high-intensity screening group showed significantly poorer BCSS compared with the low-intensity screening group (p < 0.001, HR 3.13; 95% CI 2.32-4.21). However, both multivariable analysis and propensity score matching analysis showed no significant association between the screening intensity and BCSS. CONCLUSIONS: Frequent imaging studies to detect distant metastasis were associated with earlier detection of distant metastasis, especially for lung and bone metastasis. However, intensive surveillance showed no apparent association with BCSS despite the use of currently available treatments.

Outcomes in Nonmetastatic Hormone Receptor-Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study.

BACKGROUND: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. METHODS: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. RESULTS: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. CONCLUSIONS: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Impact of residual microcalcifcations on prognosis after neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. METHODS: A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. RESULTS: There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCRw/mic group and 5.970 (1.840-19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCRw/mic group, 9.120 (2.850-29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486). CONCLUSIONS: Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.

Prevalence, treatment patterns, and prognosis of low estrogen receptor-positive (1% to 10%) breast cancer: a single institution's experience in Korea.

PURPOSE: To determine prevalence, clinicopathological characteristics, initial treatments, and outcomes associated with low estrogen receptor (ER)-expressing invasive breast cancer. METHODS: This retrospective, non-interventional database study included patients undergoing surgery with curative intent for invasive ductal or lobular breast cancer. Patients were treated between January 2003-December 2012. Demographics, clinicopathological characteristics, initial treatments, and outcomes were abstracted from patient records. Patients were categorized using immunohistochemistry to determine ER, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) levels. ER-positive patients were subclassified as ER-low (1% to 10%) and ER-high (> 10%) according to the Allred Proportion Score. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: 5930 patients were included (median follow-up, 80.9 months). Of all patients included, 117 (2.0%) had ER-low tumors: 63 (53.8%) of whom had HER2- tumors and 54 (46.2%) HER2+ tumors. Five-year DFS and OS were highest in the ER-high/HER2- cohort (94.0% and 98.6%, respectively) and lowest in the triple-negative breast cancer (TNBC; 81.3% and 90.1%) and ER-low/HER2- (85.7% and 92.1%) cohorts. Menopausal status, elevated Ki-67, higher nuclear grade, higher tumor stage, presence of lymphovascular invasion, greater regional lymph node involvement, and larger tumor size were all potential prognostic factors for shorter DFS and OS. CONCLUSION: Patients with ER-low/HER2- breast cancer had similar clinicopathological characteristics, treatments, and outcomes as patients with TNBC irrespective of disease setting. Further research is needed to understand predictive and prognostic factors associated with ER-low/HER2- disease.

The efficacy and safety of indocyanine green-hyaluronic acid mixture (LuminoMark™) for localization in patients with non-palpable breast lesions: a multi-center open-label parallel phase-2 clinical trial.

BACKGROUND: Increasing rates of breast cancer screening have been associated with an increasing frequency of non-palpable breast lesions detection. Preoperative breast lesion localization is essential for optimizing excision accuracy. This study aimed to evaluate the efficacy and safety of indocyanine green (ICG) hyaluronic acid injection as a novel mixture for localization. METHODS: We performed a prospective clinical trial with female patients who underwent surgery for non-palpable breast lesions. All patients were sequentially assigned to the control group (localization with activated charcoal), Test Group 1 (ICG-hyaluronic acid mixture 0.1 mL), or Test Group 2 (ICG-hyaluronic acid mixture 0.2 mL) by 1:1:1 ratio. RESULTS: A total of 44 patients were eligible for this study (Control Group = 14, Test Group 1 = 15, Test Group 2 = 15 patients). Fibroadenoma (n = 17, 38.6%) accounted for the largest proportion of diagnoses, and five patients (11.4%) were diagnosed with malignancies. There were no statistically significant differences in baseline characteristics among the three groups. The marking rate was over 86% in all groups, with no significant intergroup differences. Skin pigmentation was only observed in the control group. The mean accuracy of resection (the greatest diameter of the excised specimen divided by the greatest diameter of the preoperative lesion as observed using ultrasonography, with values closer to 1 reflecting a higher accuracy) was 3.7 in the control group, 2.2 in Test Group 1, and 2.1 in Test Group 2 (p = 0.037 between Controls and Test Group 1, p = 0.744 between Test Group 1 and Test Group 2, and p = 0.026 between Controls and Test Group 2). CONCLUSION: ICG-hyaluronic acid injection is a novel method that was shown to accurately localize non-palpable breast lesions and was associated with no skin pigmentation. Further research is required to apply this method to malignant breast lesions. Trial registration "A Multicenter Open-label, Parallel, Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of LuminoMark™ Inj. (Conc. for Fluorescence) Localization in Patients with Non-palpable Breast Lesions" was prospectively registered as a trial (ClinicalTrials. gov Identifier: NCT03743259, date of registration: May 29, 2018, https://clinicaltrials.gov/ct2/show/NCT03743259 ).

Correction to: ECM1 regulates cell proliferation and trastuzumab resistance through activation of EGF-signaling.

After the publication of this work [1] errors were found in Figs. 1a and 5d.

A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients.

PURPOSE: The value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established. METHODS: Pre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed. RESULTS: High pre-NAC TILs, clinical nodal stage 0-1 (cN0-1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses. CONCLUSIONS: High pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Is the high proportion of young age at breast cancer onset a unique feature of Asian breast cancer?

PURPOSE: Women with breast cancer in Asian and Western countries are similar in many respects, but there are also differences, such as in the age at onset and the proportion of breast cancer occurring at younger ages. There is controversy as to whether these differences are due to inter-racial genetic differences or to environmental or other factors. METHODS: Using the Korean Breast Cancer Society's large breast cancer registry, we investigated the causes of Koreans' unique breast cancer characteristics by examining the changes in the incidence and proportion of young-onset breast cancer (YBC) in Korea over time. We analyzed data from 108,894 patients to compare characteristics between patients with YBC and non-YBC. For a subtype analysis, we analyzed data from 85,691 patients from 2000. RESULTS: Among the 108,894 patients, 17,877 (15.5%) had YBC. The tumors associated with YBC showed aggressive clinicopathologic features. The incidence of breast cancer in Korea has increased over time, and while both YBC and non-YBC increased each year, the increase in non-YBC was more pronounced; thus, the proportion of YBC has decreased over time. By 2020, it appears that the ratio of YBC in Korea will be similar to that in Western countries. The increase in YBC was mainly due to an increase in the luminal A subtype. The incidence of other YBC subtypes did not change over time. CONCLUSIONS: Our data suggest that the current high proportion of YBC is probably not a unique feature of breast cancer in Asia but rather a transient phenomenon. Additionally, our results indirectly suggest that there were different causes for breast cancer in different age groups, suggesting the importance of using different approaches for different age groups to establish policies for preventing breast cancer.

Does guideline non-adherence result in worse clinical outcomes for hormone receptor-positive and HER2-negative metastatic breast cancer in premenopausal women?: result of an institution database from South Korea.

BACKGROUND: In this study, we observe the patterns initial palliative treatment for premenopausal patients with HR-positive/HER2-negative MBC and determine if nonadherence to clinical guidelines are associated with worse clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) in the South Korean population. METHODS: A retrospective review was performed for premenopausal patients diagnosed with HR-positive/HER2-negative MBC between October 1997 and May 2016 who received palliative systemic treatments at a large tertiary medical center. Survival outcomes were analyzed according to the palliative treatment received prior to disease progression. RESULTS: The review identified a total of 272 premenopausal patients meeting study criteria, whose median age was 39 years. Endocrine therapy was the initial treatment in 137 patients (Group 1) with chemotherapy as initial treatment in 135 patients. In the latter group, chemotherapy was continued in 78 patients (Group 2), whereas chemotherapy was switched to endocrine treatment in 57 patients prior to any disease progression (Group 3). Both PFS and OS were significantly longer for chemotherapy-endocrine therapy (median PFS 18.2 months and OS 85.2 months) than for chemotherapy-alone (median PFS 12.6 months and OS 45.5 months) or endocrine therapy-alone (median PFS 7.0 months and OS 57.3 months) (all p values < 0.01). In multivariate analysis, chemotherapy-endocrine therapy was an independent predictive value for improved PFS and OS (hazard ratio [HR] 0.33, 95% CI 0.20-0.52, p <  0.001; HR 0.38, 95% CI 0.19-0.73, p = 0.004). CONCLUSIONS: In our study population, chemotherapy alone was not objectively inferior to endocrine therapy as the initial palliative treatment. In addition, chemotherapy followed by endocrine therapy was associated with objective higher response rate than endocrine therapy alone. Further studies should explore the relationship between non-adherent treatment patterns and patient outcomes across the largely premenopausal breast cancer populations across Asian countries.

Validation of the new AJCC eighth edition of the TNM classification for breast cancer with a single-center breast cancer cohort.

PURPOSE: The new eighth edition TNM classification by the AJCC for breast cancer (BC) incorporates biologic factors and gene expression prognostic panels, in addition to traditional anatomic factors. In this study, we evaluated the prognostic value of this new staging system compared to the previous AJCC 7th edition staging system. METHODS: We conducted a retrospective analysis of women with stage I, II, or III BC who underwent curative surgery with/without adjuvant systemic therapy at Samsung Medical Center between July 2004 and December 2008. RESULTS: Of 3,208 BCs, this study was analyzed using the information of 2,790 BC patients. Hormone receptor-positive (HR+) and human epidermal growth factor 2 (HER2)- BCs were observed in 62.9% of BCs, HR+/ HER2+ in 9.3%, HR-/HER2- in 17.0%, and HR-/HER2+ in 10.8%. In survival analysis, we observed 245 distant recurrences and 198 deaths caused by BC progression. The median follow-up duration was 116.2 months. 10-year disease-specific survival (DSS) rates according to the AJCC 7th edition criteria were 97.2% of stage IA, 100% of IB, 94.9% of IIA, 87.9% of IIB, 86.4% of IIIA, 95.7% of IIIB, and 65.7% of IIIC (p < 0.001). After applying 8th edition criteria, the 10-year DSS rates were 98.1% of stage IA, 97.7% of IB, 93.8% of IIA, 92.7% of IIB, 88.2% of IIIA, 80.8% of IIIB, and 70.3% of IIIC (p < 0.001). CONCLUSIONS: The AJCC 8th edition clinical staging system provides a good prognostic value and addresses the weakness of the AJCC 7th edition, which uses only anatomical pathologic staging.

Clinical Characteristics and Prognosis of Pregnancy-Associated Breast Cancer: Poor Survival of Luminal B Subtype.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is rare and is generally defined as breast cancer diagnosed during pregnancy or within 1 year of delivery. The average ages of marriage and childbearing are increasing, and PABC is expected to also increase. This study is intended to increase understanding of the characteristics of PABC. METHODS: A database of 2,810 patients with breast cancer diagnosed when they were less than 40 years of age was reviewed. The clinicopathological factors and survival of PABC (40 patients) were compared to those of patients with young breast cancer (YBC, non-pregnant or over 12 months after delivery; 2,770 patients). RESULTS: PABC had significantly lower estrogen receptor (ER) and progesterone receptor (PR) expression (ER-positive 50.0%, PR-positive 45.0%) and higher HER2 overexpression (38.5%) than YBC. The most common subtype of PABC was triple-negative breast cancer (TNBC; 35.9%), and luminal A subtype represented only 7.7% of cases. In univariate analysis, PABC had significantly worse disease-free survival (DFS) and breast cancer-specific survival (BCSS) compared to YBC. In multivariate analysis, PABC was associated with worse BCSS (HR 4.0, 95% CI 1.2-12.9, p = 0.019) and survival, but there was no difference in DFS between PABC and YBC. In subgroup analysis by subtype, luminal B subtype of PABC showed worse DFS (HR 3.5; 95% CI 1.1-11.2, p = 0.039) and BCSS (HR 10.2, 95% CI 1.2-87.1, p = 0.035), especially with high Ki67. However, no differences were demonstrated in other subtypes. CONCLUSION: In this study, PABC showed lower expression of ER/PR, higher overexpression of HER2, fewer luminal A subtype, and more TNBC subtype compared to YBC. PABC had worse BCSS, especially luminal B subtype, compared to YBC.

Radiation-related heart disease after breast cancer radiation therapy in Korean women.

PURPOSE: To study the late cardiac toxicity of breast radiation therapy (RT) in Asian women. METHODS: Female breast cancer patients in Korea who underwent breast conservation surgery followed by RT from 1990-2012 were identified from two large registries at institution and population levels. Cumulative incidences of acute coronary events (ACE) or cardiac mortality were estimated in relation to the laterality of breast cancer using a competing risks analysis. RESULTS: In an analysis of 2577 women from a single institution, 3.7% were obese (body mass index ≥30), and 3.4% were ever-smokers. Patients with a history of hypertension, diabetes, or coronary artery disease were 17.5, 5.7, and 2.8%, respectively. The mean heart doses were 6.2 and 1.5 Gy for left- and right-sided tumors, respectively. With a median follow-up of 7 (range 1-23) years, the overall and breast cancer-specific survivals at 10 years were 94.9 and 96.5%, respectively. The 10-year cumulative incidence of ACE was 2.96%. The mean time to ACE was 5.2 ± 3.9 years (range 1-17). There was no clinically relevant difference in rates of ACE between left-sided and right-sided patients, with an adjusted hazard ratio of 1.16 (CI 0.59-2.29). An analysis of 24,235 women in a nationwide registry validated these negative findings with respect to cardiac mortality, with an adjusted hazard ratio of 1.52 (CI 0.37-6.25). Increasing age, a higher body mass index, and a history of hypertension or ischemic heart disease were identified as risk factors. CONCLUSIONS: Our findings reassure that excess risk from breast RT may be small in healthy women, most of who not smoke, weigh less, and have fewer risk factors. A validation using a larger data set of National Health Insurance Corporation is ongoing.

Identification of ganglioside GM2 activator playing a role in cancer cell migration through proteomic analysis of breast cancer secretomes.

Cancer cell secretomes are considered a potential source for the discovery of cancer markers. In this study, the secretomes of four breast cancer (BC) cell lines (Hs578T, MCF-7, MDA-MB-231, and SK-BR-3) were profiled with liquid chromatography-tandem mass spectrometry analysis. A total of 1410 proteins were identified with less than 1% false discovery rate, of which approximately 55% (796 proteins) were predicted to be secreted from cells. To find BC-specific proteins among the secreted proteins, data of immunohistochemical staining compiled in the Human Protein Atlas were investigated by comparing the data of BC tissues with those of normal tissues. By applying various criteria, including higher expression level in BC tissues, higher predicted potential of secretion, and sufficient number of tandem mass spectra, 12 biomarker candidate proteins including ganglioside GM2 activator (GM2A) were selected for confirmation. Western blot analysis and ELISA for plasma samples of healthy controls and BC patients revealed elevation of GM2A in BC patients, especially those who were estrogen receptor-negative. Additionally, siRNA-mediated knockdown of GM2A in BC cells decreased migration in vitro, whereas the overexpression of GM2A led to an increase in cell migration. Although GM2A as a diagnostic and prognostic marker in BC should be carefully verified further, this study has established the potential role of GM2A in BC progression.

Patient reporting pain intensity immediately after surgery can be associated with underlying depression in women with breast cancer.

OBJECTIVE: The aims of this study were to determine the prevalence of severe, definite depression symptoms, as measured using the Center for Epidemiological Studies Depression Scale (CES-D), and the association between high CES-D scores (i.e., ≥25) and sociodemographic and perioperative factors during perioperative period. METHODS: Among 1690 consecutive breast cancer patients who were admitted for definitive breast surgery during the study period, 1499 patients were included in this study. Patients with a past medical history of psychiatric medication or support, a plan for elective surgery due to locoregional recurrence, or any metastatic disease were excluded. The CES-D score was checked 1 day before definitive surgeries. The sociodemographic data and perioperative data were analyzed. RESULTS: The mean CES-D score was 18.5, with 24.1% (362/1499) and 56.7% (850/1499) having high CES-D scores of ≥25 and ≥16, respectively. Multivariate analysis revealed that the number of family members with any malignancy (≥2 vs. 0), sedative medication (yes vs. no), and postoperative numeric rating scale scores (persistent, severe pain vs. stably mild pain) were significantly associated factors for severe, definite depression symptoms [CES-D score of ≥25: adjusted odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.10-2.21, p = 0.013; adjusted OR = 1.65, 95% CI = 1.00-2.71, p = 0.048; and adjusted OR = 2.14, 95% CI = 1.15-3.95, p = 0.016, respectively]. CONCLUSION: Depression may increase the intensity of postoperative acute pain. Self-reporting of persistent postoperative pain intensity is potentially useful in detecting hidden depression symptoms in breast cancer patients during the perioperative period.

Cytoplasmic expression of high mobility group B1 (HMGB1) is associated with tumor-infiltrating lymphocytes (TILs) in breast cancer.

High mobility group box 1 (HMGB1) is a prototypic alarmin or damage-associated molecule inducing inflammatory mediator release and immune response. Several studies have revealed the prognostic and predictive importance of tumor-infiltrating lymphocytes (TILs) in breast cancer. The present study analyzed the expression of HMGB1 in each breast cancer subtype and the relationship between the expression level of HMGB1 and pathologic parameters including TILs. Two cohorts were studied: 575 consecutive breast cancer patients who underwent surgery between 1995 and 1998; and 767 triple negative breast cancer (TNBC) patients who underwent surgery between 2004 and 2010. The immunohistochemical expression level of HMGB1 in cytoplasm and nucleus was evaluated using tissue microarrays. High HMGB1 expression in cytoplasm was associated with high histologic grade, pT stage, and abundant TILs in the consecutive breast cancer cohort. Cytoplasmic HMGB1 expression was higher in TNBCs and HER2-positive tumors than in hormone receptor-positive tumors. In the TNBC cohort, high cytoplasmic HMGB1 expression was significantly associated with high histologic grade, abundant TILs, and high numbers of CD8+ cells. However, nuclear HMGB1 expression was not associated with histologic grade or TIL levels. Neither cytoplasmic nor nuclear expression of HMGB1 showed prognostic significance in TNBC. Cytoplasmic HMGB1 expression is associated with TIL levels in breast cancer.

Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes.

INTRODUCTION: Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment. METHODS: Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status. RESULTS: In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P <0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95 % CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95 % CI, 1.88 to 15.28) on the hormone receptor-positive and HER2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for disease free survival 2.14; 95 % CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments. CONCLUSION: Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients.

Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes.

The prognostic significance of tumor-infiltrating lymphocytes and immune signals has been described previously in triple-negative breast cancer (TNBC). Furthermore, recent studies have shown that immunologic parameters are relevant for the response to neoadjuvant chemotherapy (NAC) in breast cancer as well as for outcomes after adjuvant chemotherapy. However, immune signals are variable, and which signals are important is largely unknown. We, therefore, evaluated the expression of immune-related genes in TNBC treated with NAC. We retrospectively evaluated biopsy tissue from 55 patients with primary TNBC treated with NAC (anthracycline, cyclophosphamide, and docetaxel) against the NanoString nCounter GX Human Immunology Panel (579 immune-related genes). Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, cytokines related to T helper cell type 1 (Th1), and B cell markers was associated with a pathologic complete response (pCR). Higher expression of NFKB1, MAPK1, TRAF1, CXCL13, GZMK, and IL7R was significantly associated with pCR, higher Miller-Payne grade, and lower residual cancer burden class. Expression of NFKB1, TRAF1, and CXCL13genes, in particular, was significantly correlated with a longer disease-free survival rate. Conversely, patients those who failed to achieve a pCR showed increased expression of genes related to neutrophils. Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, Th1-related cytokines, and B cell markers is correlated with pCR and survival in TNBC patients treated with NAC. Our results suggest that the activation status of neutrophils may provide additional predictive information for TNBC patients treated with NAC.

Correlations between molecular subtypes and pathologic response patterns of breast cancers after neoadjuvant chemotherapy.

BACKGROUND: The relationship between the pathologic response patterns after neoadjuvant chemotherapy (NAC) and specific subtypes of breast cancer is unclear. METHODS: This study retrospectively analyzed 351 tumors from 348 women with breast cancer who received anthracycline and taxane-based NAC and subsequent surgery. Various histopathologic factors were assessed in the pretreatment biopsy and surgery specimens based on molecular subtypes defined by immunohistochemistry. RESULTS: The tumors without a pathologic complete response in each subtype retained their morphologic features after NAC. Lymphocytic infiltration was higher in the hormone receptor-negative (HR-) tumors than in the HR+ tumors. The HR- tumors showed more necrosis and histiocytic infiltration in the tumor bed than the HR+ tumors. The overall (including in situ carcinoma) and invasive pathologic cancer sizes were similar for the triple-negative tumors only. Although all the subtypes showed significantly reduced tumor size after NAC, the difference between the pre-NAC magnetic resonance imaging (MRI) tumor size and the overall pathologic cancer size was significantly smaller for the HR+/human epidermal growth factor receptor 2-negative (HER2-) subgroup than for the triple-negative subgroup. The triple-negative tumors showed the highest correlation between post-NAC tumor size measured by MRI and overall or invasive pathologic tumor size. CONCLUSION: The molecular subtypes of breast cancer have characteristic pathologic patterns of response to NAC.

Expression of NY-ESO-1 in Triple-Negative Breast Cancer Is Associated with Tumor-Infiltrating Lymphocytes and a Good Prognosis.

OBJECTIVES: Accumulating evidence suggests that immunotherapy has great potential for treating triple-negative breast cancer (TNBC). We analyzed the expression of NY-ESO-1, which is a potent immunogenic cancer testis antigen, and its association with clinicopathological factors in large cohorts of breast cancer patients. METHODS: A total of 623 consecutive breast cancer patients who underwent surgery between 1993 and 1998 and 612 TNBC patients who underwent surgery between 2004 and 2010 at Asan Medical Center were included. Immunohistochemical staining for NY-ESO-1 was performed using tissue microarrays. RESULTS: NY-ESO-1 was expressed in 2.6% of consecutive breast cancers, all of which were TNBC (p < 0.001). NY-ESO-1 expression was identified in 9.7% of the TNBC cohort and was significantly correlated with a higher level of tumor-infiltrating lymphocytes (TIL; p = 0.026). In survival analyses, a lower level of TIL (all, p < 0.001) and the absence of NY-ESO-1 expression (p = 0.024) were significantly associated with poor disease-free survival. Additionally, positive NY-ESO-1 expression was an independent favorable prognostic factor in TNBC patients (p = 0.046). CONCLUSIONS: NY-ESO-1 is specifically expressed in TNBC, and NY-ESO-1 expression is an independent good prognostic factor in TNBC. Evaluation of NY-ESO-1 expression in TNBC might be useful for selecting patients who may benefit from vaccination therapy and also has a prognostic significance in TNBC.

Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling.

INTRODUCTION: Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects. METHODS: In order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1. RESULTS: ECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1-induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling. CONCLUSIONS: ECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling.