On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. METHODS: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. RESULTS: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. CONCLUSIONS: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Distinct Prognosis of Minimal Residual Disease According to Breast Cancer Subtype in Patients with Breast or Nodal Pathologic Complete Response After Neoadjuvant Chemotherapy.

PURPOSE: Few studies have reported on patient prognosis according to residual cancer burden after neoadjuvant chemotherapy (NAC). Herein, we evaluated the survival of patients based on residual disease after NAC to identify subpopulations with distinct prognoses. METHODS: We retrospectively reviewed 728 patients treated with NAC from 2010 to 2017. Patients were divided into four subgroups depending on post-surgical residual disease according to the staging system: pathological complete response (pCR) (ypT0/TisN0), minimal residual disease (MRD) (ypT1mi/T1aN0 or ypT0/Tis ypN0i+/N1mic), node-only pCR (≥ ypT1b ypN0), and breast-only pCR (ypT0/Tis ≥ ypN1a). Clinicopathological characteristics and survival outcomes were analyzed by adjusting for factors affecting survival. RESULTS: Overall, 50.4% (n = 367) of patients achieved pCR, with the MRD group accounting for 16.5% (n = 120). Although age and clinical stage were not different among the study groups, histologic grade, subtypes, chemotherapy response, and local treatment showed differences. Event-free survival (EFS) and overall survival (OS) demonstrated no significant difference between the pCR and MRD groups. In the multivariate analysis, pCR status was the only significant factor in EFS, and no statistical difference was noted between the pCR and MRD groups. However, clinical stage, pCR status, and subtype significantly affected the OS. MRD showed favorable outcomes in terms of both EFS and OS in all subtypes, except for those with triple-negative breast cancer (TNBC). CONCLUSION: Patients with MRD showed outcomes comparable to those of patients who achieved pCR and may be candidates for de-escalation of post-NAC treatment, except for those with a TNBC subtype.

Oncologic Outcomes in Nipple-sparing Mastectomy with Immediate Reconstruction and Total Mastectomy with Immediate Reconstruction in Women with Breast Cancer: A Machine-Learning Analysis.

BACKGROUND: This study used a single-institution cohort, the Severance dataset, validated the results by using the surveillance, epidemiology, and end results (SEER) database, adjusted with propensity-score matching (PSM), and analyzed by using a machine learning method. To determine whether the 5-year, disease-free survival (DFS) and overall survival (OS) of patients undergoing nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) are not inferior to those of women treated with total mastectomy/skin-sparing mastectomy (TM/SSM). METHODS: The Severance dataset enrolled 611 patients with early, invasive breast cancer from 2010 to 2017. The SEER dataset contained data for 485,245 patients undergoing TM and 14,770 patients undergoing NSM between 2000 and 2018. All patients underwent mastectomy and IBR. Intraoperative, frozen-section biopsy for the retro-areolar tissue was performed in the NSM group. The SEER dataset was extracted by using operation types, including TM/SSM and NSM. The primary outcome was DFS for the Severance dataset and OS for the SEER dataset. PSM analysis was applied. Survival outcomes were analyzed by using the Kaplan-Meier method and Cox proportional hazard (Cox PH) regression model. We implemented XGBSE to predict mortality with high accuracy and evaluated model prediction performance using a concordance index. The final model inspected the impact of relevant predictors on the model output using shapley additive explanation (SHAP) values. RESULTS: In the Severance dataset, 151 patients underwent NSM with IBR and 460 patients underwent TM/SSM with IBR. No significant differences were found between the groups. In multivariate analysis, NSM was not associated with reduced oncologic outcomes. The same results were observed in PSM analysis. In the SEER dataset, according to the SHAP values, the individual feature contribution suggested that AJCC stage ranks first. Analyses from the two datasets confirmed no impact on survival outcomes from the two surgical methods. CONCLUSIONS: NSM with IBR is a safe and feasible procedure in terms of oncologic outcomes. Analysis using machine learning methods can be successfully applied to identify significant risk factors for oncologic outcomes.

Ki-67 and breast cancer prognosis: does it matter if Ki-67 level is examined using preoperative biopsy or postoperative specimen?

PURPOSE: This study aimed to identify the association between Ki-67 level and the prognosis of patients with breast cancer, regardless of the timing of Ki-67 testing (using preoperative biopsy vs. postoperative specimen). METHODS: A total of 4177 patients underwent surgery between January 2008 and December 2016. Immunohistochemical Ki-67 levels, using either preoperative (1673) or postoperative (2831) specimens, were divided into four groups using cutoff points of 10%, 15%, and 20%. RESULTS: Groups with higher-Ki-67 levels, in both the pre- and postoperative periods, showed significantly larger tumor size, higher grade, more frequent hormone receptor-negativity and human epidermal growth factor receptor 2 overexpression, and active adjuvant treatments than groups with lower-Ki-67 levels. High-Ki-67 levels were also significantly associated with poor survival, irrespective of the timing of specimen examination. CONCLUSION: Despite the problems associated with Ki-67, Ki-67 level is an important independent prognostic factor, regardless of the timing of Ki-67 testing, i.e., preoperative or postoperative testing.

Axillary response according to neoadjuvant single or dual human epidermal growth factor receptor 2 (HER2) blockade in clinically node-positive, HER2-positive breast cancer.

Incorporating dual human epidermal growth factor receptor 2 (HER2) blockade into neoadjuvant systemic therapy (NST) led to higher response in patients with HER2-positive breast cancer. However, axillary response to treatment regimens, including single or dual HER2 blockade, in patients with clinically node-positive breast cancer remains uncertain. Our study aimed to examine the pathologic axillary response according to the type of NST, that is, single or dual HER2 blockade. In our study, 546 patients with clinically node-positive, HER2-positive breast cancer who received NST followed by axillary surgery were retrospectively selected and divided into three groups: chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab. The primary outcome was the axillary pathologic complete response (pCR). Among 471 patients undergoing axillary lymph node dissection, the axillary pCR rates were 43.5%, 74.5% and 68.8% in patients who received chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab, respectively. There was no difference in axillary pCR rates between patients who received single or dual HER2 blockade (P = .379). Among patients receiving chemotherapy + trastuzumab, patients without breast pCR had the greatest risk for residual axillary metastases (relative risk, 9.8; 95% confidence interval, 3.2-14.9; P < .0001). In conclusion, adding trastuzumab to chemotherapy increased the axillary pCR rate in patients with clinically node-positive, HER2-positive breast cancer; furthermore, dual HER2-blockade with trastuzumab and pertuzumab did not elevate the axillary response compared with trastuzumab alone. Breast pCR could be a strong predictor for axillary pCR in clinically node-positive patients treated with HER2-targeting therapy.

Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.

BACKGROUND: This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). METHODS: The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally. RESULTS: A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. CONCLUSION: The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.

Survival of Breast-Conserving Surgery Plus Radiotherapy versus Total Mastectomy in Early Breast Cancer.

BACKGROUND: Breast-conserving surgery (BCS) has been reported to have better survival rates when compared with total mastectomy (TM) in early breast cancer. We evaluated the long-term outcomes of Korean women with early breast cancer who underwent either BCS plus radiotherapy (RT) or TM. METHODS: In this population-based study, we evaluated 45,770 patients from the Korean Breast Cancer Registry (KBCR) who were diagnosed with early breast cancer, and divided them into the BCS + RT and TM groups. To minimize bias caused by factors other than the surgical method, we used exact match pairing of prognostic factors. We compared the 10-year overall survival (OS) and breast cancer-specific survival (BCSS) before and after exact matching. As the KBCR is a multicenter, online-based registry program, we used the Asan Medical Center (AMC) database, a single-center database, to validate the results from the KBCR database. RESULTS: In both the KBCR and AMC cohorts, the BCS + RT group showed better OS and BCSS than the TM group, before and after exact matching. For the KBCR cohort after exact matching, the hazard ratios for OS and BCSS were 1.541 (95% confidence interval [CI] 1.392-1.707, p < 0.001) and 1.405 (95% CI 1.183-1.668, p < 0.001), respectively, favoring the BCS + RT group. For the AMC cohort after exact matching, the hazard ratios for OS and BCSS were 1.854 (95% CI 1.476-2.328, p < 0.001) and 1.807 (95% CI 1.186-2.752, p = 0.006), respectively. CONCLUSIONS: Our results suggest that BCS + RT is at least equivalent to TM in terms of OS and may affect treatment decisions in early breast cancer patients.

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.

BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

Correction to: Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

In the original publication of the article, under the Results section, subheading "Patient survival", the second sentence that reads as "The 6-month PFS was 92.4%, 81.8%, and 93.3% and the one-year PFS was 72.0%, 88.9%, and 78.9% in Groups 1-3, respectively." should read as "The 6-month PFS was 82.8%, 75.0%, and 68.0% and the one-year PFS was 77.0%, 62.0%, and 63.8% in Groups 1-3, respectively.".

Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

PURPOSE: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia. METHODS: A consecutive cohort of ER( +)/HER2( -) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial. RESULTS: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3-4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1. CONCLUSIONS: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice.

Intermediate HER2 expression is associated with poor prognosis in estrogen receptor-positive breast cancer patients aged 55 years and older.

PURPOSE: An antibody-drug conjugate targeting HER2, DS8201, has shown clinical activity against breast cancer with low-level HER2 expression. We aimed to evaluate the prognostic impact of intermediate HER2 expression in estrogen receptor (ER)+ early breast cancer (EBC) and metastatic breast cancer (MBC) cohorts. METHODS: We analyzed prospectively collected data from EBC and MBC cohorts at Yonsei Cancer Center. Patients with HER2 immunohistochemistry (IHC) 0 ~ 1+ were assigned to the HER2-negative group, and patients with IHC 2+ and in situ hybridization (ISH)-negativity were assigned to the HER2-intermediate group. After the exclusion of HER2 IHC 3+ or ISH+ patients, a total of 2657 EBC and 535 MBC patients were analyzed. RESULTS: In total, 654 (24.6%) EBC and 166 (31.0%) MBC patients were classified in the HER2-intermediate group. The HER2-intermediate patients more frequently tended to have progesterone receptor (PR)-negativity and higher nuclear grade in the EBC cohort, and showed a higher proportion of patients aged ≥ 55 years compared with the HER2-negative group in the MBC cohort. The HER2-intermediate patients showed significantly poorer recurrence-free survival (RFS) compared to the HER2-negative patients in the EBC cohort (p = 0.044). Notably, intermediate HER2 expression predicted poorer RFS in EBC patients aged ≥ 55 years (hazard ratio 1.95; p = 0.042) in multivariate Cox analysis but did not affect RFS in those aged < 55 years. In line with the EBC cohort results, intermediate HER2 expression predicted poorer overall survival (OS) in MBC patients aged ≥ 55 (hazard ratio 1.45; p = 0.044) without affecting OS of those aged < 55 years. CONCLUSION: Intermediate HER2 expression is an independent predictor of poor prognosis in both ER+ EBC and MBC patients aged ≥ 55 years. The clinical efficacy of new HER2-targeting antibody-drug conjugates needs to be validated in this high-risk subset of ER+ breast cancer patients.

Adjuvant chemotherapy and survival among patients 70 years of age and younger with node-negative breast cancer and the 21-gene recurrence score of 26-30.

BACKGROUND: The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18-30, particularly those with RS 26-30, are not known. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18-30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox's proportional hazards model. RESULTS: Among the breast cancer patients with the RS 18-30, 21% of them had RS 26-30. Compared to breast cancer patients with RS 18-25, patients with RS 26-30 had more aggressive tumor characteristics and chemotherapy use and increased risk of breast cancer-specific mortality and overall mortality. In breast cancer patients who were aged ≤ 70 years and had RS of 26-30, chemotherapy administration was associated with a 32% lower risk of breast cancer-specific mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47-0.99) and a 42% lower risk of overall mortality (HR, 0.58; 95% CI, 0.44-0.76). Survival benefits were most pronounced in breast cancer patients who were younger or had grade III tumor. CONCLUSIONS: The 21-gene RS of 18-30 showed heterogeneous outcomes, and the RS 26-30 was a significant prognostic factor for an increased risk of mortality. Adjuvant chemotherapy could improve the survival of node-negative, hormone receptor-positive, and HER2-negative breast cancer patients with the 21-gene RS 26-30 and should be considered for patients, especially younger patients or patients with high-grade tumors.

Prevalence of breast cancer-related risk factors in underweight premenopausal women: the Korea National Health and Nutrition Examination Survey IV-VI.

PURPOSE: This study aimed to examine the prevalence and trends of breast cancer-related risk factors and characteristics in premenopausal underweight Korean women according to birth year cohort. METHODS: Socioeconomic and breast cancer-related risk factors were investigated in 13,415 premenopausal women using nationwide cross-sectional surveys performed between 2007 and 2015. Underweight was defined as body mass index < 18.5 kg/m2. Multivariable models were created using complex sample procedures. RESULTS: Underweight women comprised 9.5% of the sample. Compared with those who were obese or of normal weight, underweight women were characterized by younger age, higher rate of metropolitan residence, higher economic status, more education, higher rates of non-manual employment and unmarried status, lower rate of early menarche, higher rates of nulliparity, lower parity, alcohol consumption, and never having breastfed, and lower levels of high physical activity. Multivariable analysis showed that underweight women had a significantly lower rate of early menarche, lower parity, higher nulliparity, older age at first delivery, and lower levels of high physical activity compared to premenopausal women with normal weight. These trends were more apparent among women born in recent years. CONCLUSIONS: Underweight Korean premenopausal women exhibit distinctive features associated with an increased risk of breast cancer, except for a lower rate of early menarche. These associations were prominent in recent generations. Assessment of the association between underweight and premenopausal breast cancer risk should focus on promoting healthy lifestyles to reduce breast cancer risk.

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

BACKGROUND: This 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. METHODS: The 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. RESULTS: Univariable 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. CONCLUSION: pN1mi 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.

Factors predictive of occult nipple-areolar complex involvement in patients with carcinoma in situ of the breast.

OBJECTIVES: To investigate predictors of occult nipple-areolar complex (NAC) involvement in patients with carcinoma in situ (CIS) and to validate an online probability calculator (CancerMath; www.lifemath.net/cancer/breastcancer/nipplecalc/index.php). METHODS: Mastectomized patients with CIS (n = 104) were retrospectively selected. Clinicopathology and preoperative mammography, ultrasound, and magnetic resonance imaging (MRI) findings were analyzed. RESULTS: Histopathological NAC-positivity was confirmed in 20 (19.2%) patients. Short nipple-tumor distance and suspicious extension to the nipple by mammography were significant but ultrasound was not significant to predict NAC involvement. NAC-positive cases had MRI findings of shorter nipple-tumor distance in both the early and delayed phases. Multivariable regression model showed age >50 years and shorter tumor-nipple distance on the delay phase of MRI were statistically significant predictors of NAC involvement. Area under the receiver operating characteristics curve (AUC) was 0.618 when calculated by CancerMath; however, an AUC of 0.954 was achieved when distance and age were applied together as predictor. CONCLUSIONS: Mammographic and MRI findings were significant for predicting NAC involvement, with distance of the tumor from the nipple in delay phase MRI the most significant predictor of NAC involvement. Therefore, breast MRI could be beneficial for planning nipple-sparing mastectomy in patients with CIS.

Breast ultrasonography for detection of metachronous ipsilateral breast tumor recurrence.

BACKGROUND: Early detection of recurrence improves the survival rate of patients treated with breast conservation therapy (BCT). Therefore, ultrasonography (US) may be useful for metachronous ipsilateral breast tumor recurrence (MIBTR) obscured on mammography by dense breast tissue and distortion. PURPOSE: To evaluate clinical, radiologic, and pathologic findings of MIBTR retrospectively, and to assess the role of surveillance US additional to mammography for MIBTR detection. MATERIAL AND METHODS: During 2000 to 2012, 28 MIBTR were collected and reviewed among 2958 women treated for primary breast cancer with conservation surgery. The detection rates of imaging studies for identifying metachronous ipsilateral lesions were assessed and compared. MIBTR tumor staging was evaluated according to imaging modality for detection of MIBTR, palpability, and recent imaging surveillance. RESULTS: No significant difference was observed in the detection rate between mammography and US for overall MIBTR (84.2% vs. 85.7%; P = 0.898) or non-palpable MIBTR (88.2% vs. 81.0%; P = 0.566). US alone identified 33.3% of non-palpable MIBTRs (seven of 21). Among these cases, two had negative mammograms. All 14 MIBTRs with recent imaging surveillance were stage T2 or less, and all seven MIBTRs detected by US alone were in situ or T1; 33% of MIBTRs without recent imaging surveillance were T3 or T4. CONCLUSION: The overall MIBTR detection rate by US was not higher than the detection rate of mammography, although combined surveillance with US and mammography found MIBTRs slightly earlier than mammography alone.

Serum 25-hydroxyvitamin D deficiency and increased risk of breast cancer among Korean women: a case-control study.

Despite the emerging literature supporting the beneficial role of vitamin D on various health outcomes including carcinogenesis, current evidence on the association between vitamin D and breast cancer is still largely inconsistent. Furthermore, this relationship is particularly under explored among Asian population. We conducted a large case-control study with Korean women. We obtained and compared serum 25-hydroxyvitamin D (25(OH)D) between breast cancer patients (N = 3634) and general population (N = 17,133). Moreover, we further examined the association between serum 25(OH)D and breast cancer risk stratified by menopausal status and hormone receptor (HR) status of the tumor. Adjusted odds ratio (OR) for breast cancer comparing women with deficient level of serum 25(OH)D to women with sufficient level of serum 25(OH)D was 1.27 [95 % confidence interval (CI) 1.15-1.39]. This association did not significantly vary by menopausal status [pre-menopause: 1.26 (95 % CI 1.09-1.45) vs. post-menopause: 1.25 (95 % CI 1.10-1.41)]. When stratified by HR status, the inverse association remained significant in both positive and negative statuses. However, this association was more pronounced in HR-negative breast cancer, particularly with triple-negative breast cancer patients (1.45, 95 % CI 1.15-1.82). Given the growing burden of breast cancer in Asia and dearth of studies examining the association between vitamin D and breast cancer risk in Asian women thus far, this study provides a meaningful evidence for potential preventive effect of vitamin D on breast cancer for this particular population.

Negative Impact of Aromatase Inhibitors on Proximal Femoral Bone Mass and Geometry in Postmenopausal Women with Breast Cancer.

Aromatase inhibitors (AIs), the standard therapy for estrogen receptor- or progesterone receptor-positive breast cancer in postmenopausal women, lead to increased hip fractures in breast cancer patients. To investigate the mechanism of increased incidence of hip fractures in breast cancer patients treated with AIs, we evaluated bone mineral density (BMD) in the cortical and trabecular compartments and assessed femoral geometry using quantitative computed tomography (QCT) in breast cancer patients. In total, 249 early breast cancer patients who underwent QCT in their fifties (mean age 54.3 years) were retrospectively analyzed. Proximal femoral BMD and geometrical parameters were compared. In all regions of the proximal femur, cortical areal BMDs were lower in the AI group than in the non-AI group (p < 0.05). Cortical thickness of the femoral neck, trochanter, and total hip was significantly lower in the AI group compared with the non-AI group (p < 0.05). Analysis of the narrowest section of the femoral neck showed significantly thinner cortical bone and smaller cortical area in the AI group than in the non-AI group (p < 0.05), especially in the superoposterior quadrant. Bone strength parameters in the femoral neck, such as the section modulus and cross-sectional moment of inertia, were significantly lower in the AI group than in the non-AI group (p < 0.05). In conclusion, AI treatment in breast cancer patients is associated with deterioration of femoral cortical BMD and geometry, which could contribute in site-specific weakened bone strength and increased incidence of hip fractures.

Evaluation with 3.0-T MR imaging: predicting the pathological response of triple-negative breast cancer treated with anthracycline and taxane neoadjuvant chemotherapy.

BACKGROUND: Triple-negative breast cancer (TNBC) which expresses neither hormonal receptors nor HER-2 is associated with poor prognosis and shorter survival. Several studies have suggested that TNBC patients attaining pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) show a longer survival than those without pCR. PURPOSE: To assess the accuracy of 3.0-T breast magnetic resonance imaging (MRI) in predicting pCR and to evaluate the clinicoradiologic factors affecting the diagnostic accuracy of 3.0-T breast MRI in TNBC patients treated with anthracycline and taxane (ACD). MATERIAL AND METHODS: This retrospective study was approved by the institutional review board; patient consent was not required. Between 2009 and 2012, 35 TNBC patients with 3.0-T breast MRI prior to (n = 26) or after (n = 35) NAC were included. MRI findings were reviewed according to pCR to chemotherapy. The diagnostic accuracy of 3.0-T breast MRI for predicting pCR and the clinicoradiological factors affecting MRI accuracy and response to NAC were analyzed. RESULTS: 3.0-T MRI following NAC with ACD accurately predicted pCR in 91.4% of TNBC patients. The residual tumor size between pathology and 3.0-T MRI in non-pCR cases showed a higher correlation in the Ki-67-positive TNBC group (r = 0.947) than in the Ki-67 negative group (r = 0.375) with statistical trends (P = 0.069). Pre-treatment MRI in the non-pCR group compared to the pCR group showed a larger tumor size (P = 0.030) and non-mass presentation (P = 0.015). CONCLUSION: 3.0-T MRI in TNBC patients following NAC with ACD showed a high accuracy for predicting pCR to NAC. Ki-67 can affect the diagnostic accuracy of 3.0-T MRI for pCR to NAC with ACD in TNBC patients.

Subcellular localization of Mdm2 expression and prognosis of breast cancer.

BACKGROUND: Mouse double minute 2 (Mdm2) is a negative regulator of the tumor suppressor p53. The p53-Mdm2 pathway may play a role in cancer development and prognosis, although the role of p53-Mdm2 in breast cancer remains unclear. METHODS: p53 and Mdm2 expressions were determined by immunohistochemistry of tissue microarrays of 865 breast cancer patients who underwent surgery. Clinicopathological characteristics and survival data were analyzed. Mdm2 expression was categorized into four groups: negative, cytoplasm positive, nucleus positive, and concurrent nuclear and cytoplasm positive (N+&C+). RESULTS: Negative, cytoplasm-positive, nucleus-positive, and N+&C+ expressions of Mdm2 were observed in 59.2, 10.9, 27.8, and 2.1 % of patients, respectively. The N+&C+ group was associated with larger tumor size, higher grade, negativity for estrogen and progesterone receptors, HER2 positivity, high Ki-67 index, p53 positivity, and triple negative breast cancer. p53-positive tumors showed poorer overall survival than p53-negative tumors. The nucleus-positive and N+&C+ groups showed poorer disease-free survival than the negative and cytoplasm-positive groups. In multivariate analysis, nuclear Mdm2 expression including the N+&C+ group was significantly related to poor prognosis. CONCLUSIONS: Concurrent nuclear and cytoplasmic Mdm2 expression was an independent prognostic factor in patients with breast cancer. Subcellular localization of Mdm2 expression should be considered in the evaluation of Mdm2 in breast cancer.