Occurrence and outcome of de novo metastatic breast cancer by subtype in a large,diverse population

Purpose

To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression.

Methods

We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I–III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality.

Results

Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17–1.42; HR?/HER2+: OR 1.40, 95 %CI 1.25–1.57, vs. HR+/HER2?). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50–3.24) and HR?/HER2+ (RH 1.60, 95 % CI 1.37–1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2? breast cancer.

Conclusions

De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes.

     

The prognostic analysis of clinical breast cancer subtypes among patients with liver metastases from breast cancer

Background

To determine whether the inferior outcome noted with triple-negative breast cancer (TNBC) reflects a higher risk population among patients with breast cancer liver metastases.

Methods

A total of 123 patients with breast cancer liver metastases diagnosed at Tianjin Medical University Cancer Hospital were included in this study. Breast cancer subtype was assigned using immunohistochemistry or fluorescence in situ hybridization: hormone receptor (HR) positive (+)/human epidermal growth factor receptor 2 (HER2) negative (?), HR+/HER2+, HR?/HER2+ and triple-negative subtype. Clinical features and survival were evaluated in different subtypes.

Results

The median age at breast cancer diagnosis was 47 years (range, 23–67 years). Breast cancer subtype was confirmed in all patients (39.8% with HR+/HER2?, 24.4% with HR+/HER2+, 15.3% with HR?/HER2+ and 20.3% with TNBC). The median overall survival after liver metastases was 29 months (range, 4–89 months), and the overall 1-, 2- and 3-year survival rate was 68.3, 48.0 and 34.1%, respectively. Survival was found to be impacted by breast cancer subtype (P = 0.001), and was shortest for patients with TNBC. Time to liver metastases (TTLM) less than 24 months and liver metastasis lesions ≥3 were found to be important predictors of poor survival after liver metastases (P = 0.009 and 0.001, respectively).

Conclusions

The results indicate that clinical breast cancer subtype remains an independent prognostic predictor among patients with breast cancer liver metastases. Liver metastases arising from TNBC confers the worst prognosis, and novel agents capable of controlling intrahepatic and extrahepatic TNBC are needed.     

Association of race/ethnicity,socioeconomic status,and breast cancer subtypes in the National Cancer Data Base (2010–2011)

To estimate the odds of breast cancer subtypes in minority populations versus non-Hispanic (NH) whites stratified by socioeconomic status (SES) [a composite of individual-level SES (insurance status) and area-level SES (median household income quartile from 2000 U.S. Census data)] using a large nationwide cancer database. We used the National Cancer Data Base to identify breast cancer cases diagnosed in 2010 and 2011, the only 2 years since U.S. cancer registries uniformly began collecting HER2 results. Breast cancer cases were classified into five subtypes based on hormone receptor (HR) and HER2 status: HR+/HER2?, HR+/HER2+, HR?/HER2+ (HER2-overexpressing), HR?/HER2? (TN), and unknown. A polytomous logistic regression was used to estimate odds ratios (ORs) comparing the odds of non-HR+/HER2-subtypes to HR+/HER2? for racial/ethnic groups controlling for and stratifying by SES, using a composite of insurance status and area-level income. Compared with NH whites, NH blacks and Hispanics were 84 % (OR = 1.84; 95 % CI 1.77–1.92) and 17 % (OR = 1.17; 95 % CI 1.11–1.24) more likely to have TN subtype versus HR+/HER2?, respectively. Asian/Pacific Islanders (API) had 1.45 times greater odds of being diagnosed with HER2-overexpressing subtype versus HR+/HER2? compared with NH whites (OR = 1.45; 95 % CI 1.31–1.61). We found similar ORs for race in high and low strata of SES. In a large nationwide hospital-based dataset, we found higher odds of having TN breast cancer in black women and of HER2-overexpressing in API compared with white women in every level of SES.     

Tumor histological subtyping determined by hormone receptors and HER2 status defines different pathological complete response and outcome to dose-dense neoadjuvant chemotherapy in breast cancer patients

Purpose

To assess the impact in pathological complete response (pCR) and outcome of two dose-dense neoadjuvant chemotherapy (DDNC) regimens among different histological subtypes determined by hormonal receptor (HR) and HER2 status in breast cancer patients.

Methods

A total of 127 breast cancer patients were treated with DDNC in two prospective studies. A: adriamycin 40 mg/m² on day (d) 1 plus paclitaxel 150 mg/m² and gemcitabine 2,000 mg/m² on d2 for six cycles (n = 54). B: epirubicin 90 mg/m², cyclophosphamide 600 mg/m² on d1 for three cycles, followed by paclitaxel 150 mg/m² and gemcitabine 2,500 mg/m² on d1 ± trastuzumab according to HER2 status (n = 73). Histological subtypes of breast cancer were 49 % HR+/HER2?, 17.5 % HR+/HER2+, 13.5 % HR?/HER2+ and 20 % HR?/HER2?.

Results

pCR (absence of invasive cells in breast and lymph node) was achieved in 35 patients (28 %). The pCR rate was significantly different between histological subtypes: HR+/HER2? (9 %), HR+/HER2+ (23 %), HR?/HER2+ (50 %), HR?/HER2? (56 %) (p < 0.001). The median follow-up was 81 months (r: 15–150 months). HR?/HER2? tumor subtype had a significantly worse DFS compared to HR+/HER2? (p = 0.02), RH+/HER2+ (p = 0.04) and HR?/HER2+ tumor subtypes (p = 0.02). HR?/HER2? tumor subtype had a significantly shorter OS compared to HR+/HER2? (p = 0.007), RH+/HER2+ (p = 0.05), and HR?/HER2+ (p = 0.03) tumor subtypes. However, no significant difference was observed in DFS and OS among HR?/HER2? tumors that achieved a pCR.

Conclusions

HR?/HER2? and HR?/HER2+ subtypes had a high pCR rate to DDNC. HR?/HER2? tumors had a worse outcome compared to other tumor subtypes but no significant difference was observed among HR?/HER2? tumors that achieved a pCR.     

Pazopanib efficacy in recurrent central nervous system hemangiopericytomas

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996–2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan–Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2?/HR+, 24.8% TN, 22.2% HER2+/HR? and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25–85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2?/HR+ 5.3 years (95% CI 4.6–5.9), HER2+/HR+ 4.4 years (95% CI 3.4–5.2), HER2+/HR? 2.6 years (95% CI 2.2–3.1) and TN 2.2 years (95% CI 1.9–2.7) (p?<?0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p?<?0.001), and between HER2+ and HER2? tumors (3.2 vs. 3.8 years, p?=?0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio?=?1.36 for ER, p?=?0.013, 1.31 for PR, p?=?0.021, and 1.01 for HER2+ vs. HER2? tumors, p?=?0.880). HR? and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.     

Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer

Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to the combination of hormone receptor (HR) and HER2 status; #2: Intrinsic subtype classification (Triple Negative (TN), HER2, Luminal B and Luminal A). Results: Both subtype classifications yielded prognostic and predictive information. HR +/HER2? patients (and Luminal A patients) had a significantly better outcome than the other subgroups of patients. The superiority of FEC-P over FEC was clearly more marked in HR?/HER2? patients (TN patients), particularly in the subset with basal phenotype (TN and either EGFR+ or cytokeratins 5/6+). The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel.     

African American patients with breast cancer have worse prognosis than white patients in certain subtypes and stages

Purpose

Racial disparity of breast cancer in each subtype and substage is not clear.

Methods

We reviewed 156,938 patients with breast cancer from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Breast cancer was subtyped by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status as HR+/HER2?, HR+/HER2+, HR?/HER2+, and HR?/HER2?.

Results

African American (AA) patients had worse overall survival (OS) and breast cancer cause-specific survival (BCSS) in HR+/HER2? stages III and IV breast cancer and HR?/HER2+ stage IV cancer; they had worse OS but not BCSS in HR+ /HER2? stage II cancer and HR?/HER2? stage II cancer.

Conclusion

AA patients with breast cancer had worse survival in certain subtype and stage, especially in ER+ breast cancer.

     

HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients

Breast cancer is a highly heterogeneous malignancy. The triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) breast cancer subtypes are highly aggressive and are associated with a poor prognosis. The therapeutic targets for TNBC remain undefined, and many patients with the HER2 subtype acquire resistance to therapy after prolonged treatment. The objective of this study was to evaluate the prognostic significance of HER3 expression in invasive breast carcinoma. We established matched tissue microarray (TMA) blocks and clinical data from 950 cases of invasive breast carcinoma with long-term clinical follow-up data (median 109.7 months). Using the TMAs, we characterized the expression of ER, PR, HER2, EGFR, and HER3 by immunohistochemistry. Each case was classified as one of four IHC-based subtypes based on the expression of hormonal receptor (HR) and HER2. The clinicopathological characteristics and survival of 950 patients were analyzed by subtype. In the TNBC subtype, the HER3(+) group showed poorer disease-free survival (DFS, P = 0.010) and overall survival (OS, P = 0.015) than the HER3(?) group. In the HER2 subtype, the HER3(+) group also showed poorer DFS (P = 0.022) and OS (P = 0.077) than the HER3(?) group. However, there was no difference in patients with HR-positive breast cancer. HER3 expression was associated with poor DFS in both the TNBC and HER2 subtypes and poor OS in the TNBC subtype. HER3 overexpression is an important prognostic marker in hormone receptor-negative breast cancer, and further study is needed to clarify the role of HER-3 targeted treatment.     

Prognostic factors for survival in metastatic breast cancer by hormone receptor status

Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003–2006 treated with curative intent who developed MBC within 5 years of follow-up were selected from the Netherlands cancer registry (N = 2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR?) tumours was 8 months, compared to 19 months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR? patients, but not in HR+ patients. HER2-Neu positive status was associated with better survival in both HR+ and HR? patients, although the association was stronger in HR? patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR? patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients.     

Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer

The clinical behavior of human epidermal growth factor 2 (HER2)-positive breast cancer, including pathologic complete response rate and pattern of relapse and metastasis, differs substantially according to hormone receptor (HR) status. We investigated various histopathologic features of HER2-positive breast cancer and their correlation with HR status. We retrospectively analyzed tumors of 450 HER2-positive breast cancer patients treated with chemotherapy and 1 year of trastuzumab. HR?/HER2+ tumors showed higher nuclear grade, less tubule formation, higher histologic grade, frequent apocrine features, diffuse and abundant lymphocytic infiltration, strong HER2 immunohistochemical staining (3+), higher average HER2 copy number and HER2/CEP17 ratio, the absence of HER2 genetic heterogeneity, and greater p53 expression than HR+/HER2+ tumors. An inverse correlation was observed between estrogen receptor or progesterone receptor Allred score and average HER2 copy number or HER2/CEP17 ratio. The percentage of ductal carcinoma in situ (DCIS) within the tumor was negatively correlated with ER Allred score, but positively correlated with average HER2 copy number and HER2/CEP17 ratio. Pathologic tumor size and DCIS percentage also showed a significant inverse correlation. Ratio of metastatic to total examined lymph node number was significantly correlated with average HER2 copy number and HER2/CEP17 ratio. High pT stage (hazard ratio, 2.370; p = 0.027), the presence of lymphovascular invasion (hazard ratio, 2.806; p = 0.005), and HR negativity (hazard ratio, 2.202; 1.074–4.513; p = 0.031) were found to be independent prognostic indicators of poor disease-free survival. In conclusion, HR+/HER2+ and HR?/HER2+ breast cancer showed distinct histopathologic features that may be relevant to their distinct clinical behavior.     

Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience

Purpose

Gene expression profiling studies have identified several breast cancer subtypes associated with markedly different clinical outcomes. In general, patients with stage I breast cancer have excellent outcomes. We assessed the clinicopathological characteristics and outcomes of patients with T1N0M0 breast cancer according to molecular subtype.

Methods

Seven hundred and sixty-two T1N0M0 breast cancer patients undergoing curative surgery between January 1990 and December 2007 were analyzed. Subtypes were classified according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status as follows: HR+/HER2−, HR+/HER2+, HR−/HER2− (triple-negative, TN), and HR−/HER2+.

Results

The distribution of subtypes was HR+/HER2−, 56.6%; HR+/HER2+, 10.1%; TN, 20.1%; and HR−/HER2+, 13.3%. Marked differences were observed among subtypes in multifocality/multicentricity, histological grade, extensive intraductal components, p53 expression and the Ki-67 index. There were differences in recurrence-free survival and overall survival among patients with different molecular subtypes (log-rank p < 0.001 and 0.024, respectively). By multivariate analysis, lymphovascular invasion and classification of molecular subtype were independent predictors of recurrence (p = 0.003 and 0.043, respectively). The TN subtype showed significantly worse recurrence-free survival compared to the HR+/HER2− subtype (hazard ratio, 4.54; 95% confidence interval, 1.60-12.86; p = 0.004).

Conclusion

Patients with T1N0M0 breast cancer, a group with generally favorable clinical outcomes, had prognoses that were associated with the molecular subtype. The TN subtype was an independent predictor for recurrence in patients with T1N0M0 breast cancer.     

Patterns of relapse and metastatic spread in HER2-overexpressing breast cancer according to estrogen receptor status

Purpose

The primary aim of this study was to compare the relapse patterns of estrogen receptor (ER)-positive and ER-negative patients with HER2-overexpressing breast cancer. A secondary aim was to distinguish the preferential primary site of metastases in HER2-overexpressing breast cancer.

Methods

Out of 886 patients treated for metastatic breast cancer (MBC) between January 1995 and December 2006, 269 patients with HER2-positive tumors were identified. Of these, 198 patients with relapsed breast cancer following surgery were included in this study. Rates and patterns of relapse and metastatic spread in HER2+/ER+ and HER2+/ER? patients were analyzed. This analysis was evaluated by the validation patients’ cohort of our institute prospectively.

Results

Median relapse-free survival was longer in the HER2+/ER+ group than in the HER2+/ER? group (32.0 vs. 19.5 months, p = 0.0012). The peak of recurrence occurred at 12 months after surgery in the HER2+/ER? patients. The peak of relapse was later and the level was lower in the HER2+/ER+ patients (66 and 78 months following surgery) than in the HER2+/ER? patients (33 and 39 months following surgery, respectively). This result was reproduced by the validation cohort with great similarity. Young age [hazard ratio (HR) 1.59, p = 0.002], TNM stage 3 (HR 1.51, p = 0.005), and ER-negativity (HR 1.68, p < 0.0001) were identified as independent risk factors for relapse. Severe bone metastasis (HR 4.48, p = 0.028) and massive hepatic metastasis (HR 5.24, p = 0.043) were identified as independent risk factors for early relapse.

Conclusions

Our study shows that HER2-overexpressing breast cancer displays characteristic patterns of relapse and metastatic spread depending on ER status.     

Risk of death from cardiovascular disease following breast cancer: a systematic review

Purpose

To analyze the prognostic influence of metastatic pattern (MP) compared with other biologic and clinical factors in stage IV breast cancer at initial diagnosis (BCID) and evaluate factors associated with specific sites of metastases (SSM).

Methods

We evaluated women with stage IV BCID with known metastatic sites, reported to the Surveillance, Epidemiology and End Results program from 2010 to 2013. MP was categorized as bone-only, visceral, bone and visceral (BV), and other. Univariate and multivariate analyses determined the effects of each variable on overall survival (OS). Logistic regression examined factors associated with SSM.

Results

We included 9143 patients. Bone represented 37.5% of patients, visceral 21.9%, BV 28.8%, and other 11.9%. Median OS by MP was as follows: bone 38 months, visceral 21 months, BV 19 months, and other 33 months (P < 0.0001). Univariate analysis showed that higher number of metastatic sites had worse prognosis. In multivariate analysis, older age (hazard ratio 1.9), black race (hazard ratio 1.17), grade 3/4 tumors (hazard ratio 1.6), triple-negative (hazard ratio 2.24), BV MP (hazard ratio 2.07), and unmarried patients (hazard ratio 1.25) had significantly shorter OS. As compared with HR+/HER2? tumors, triple-negative and HR?/HER2+ had higher odds of brain, liver, lung, and other metastases. HR+/HER2+ had higher odds of liver metastases. All three subtypes had lower odds of bone metastases.

Conclusions

There were substantial differences in OS according to MP. Tumor subtypes have a clear influence among other factors on SSM. We identified several prognostic factors that could guide therapy selection in treatment naïve patients.

     

The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer

Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi-institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4 months (p < 0.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7 months (p < 0.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0 months (p < 0.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes.     

Breast cancer subtype affects patterns of failure of brain metastases after treatment with stereotactic radiosurgery

We investigate the variance in patterns of failure after Gamma Knife? radiosurgery (GKRS) for patients with brain metastases based on the subtype of the primary breast cancer. Between 2000 and 2010, 154 breast cancer patients were treated with GKRS for brain metastases. Tumor subtypes were approximated based on hormone receptor (HR) and HER2 status of the primary cancer: Luminal A/B (HR+/HER2(?)); HER2 (HER2+/HR(?)); Luminal HER2 (HR+/HER2+), Basal (HR(?)/HER2(?)), and then based on HER2 status alone. The median follow-up period was 54?months. Kaplan?CMeier method was used to estimate survival times. Multivariable analysis was performed using Cox regression models. Median number of lesions treated was two (range 1?C15) with a median dose of 20?Gy (range 9?C24?Gy). Median overall survival (OS) was 7, 9, 11 and 22?months for Basal, Luminal A/B, HER2, and Luminal HER2, respectively (p?=?0.001), and was 17 and 8?months for HER2+ and HER(?) patients, respectively (p?<?0.001). Breast cancer subtype did not predict time to local failure (p?=?0.554), but did predict distant brain failure rate (76, 47, 47, 36?% at 1?year for Basal, Luminal A/B, HER2, and Luminal HER2 respectively, p?<?0.001). An increased proportion of HER2+ patients experienced neurologic death (46 vs 31?%, p?=?0.066). Multivariate analysis revealed that HER2+ patients (p?=?0.007) independently predicted for improved survival. Women with basal subtype have high rates of distant brain failure and worsened survival. Our data suggest that differences in biologic behavior of brain metastasis occur across breast cancer subtypes.     

Leptomeningeal metastases from breast cancer: intrinsic subtypes may affect unique clinical manifestations

Leptomeningeal metastasis (LM) usually occurs late during the course of breast cancer. The aim of this study was to characterize the clinical features and outcomes of LM based on breast cancer subtypes in conjunction with brain parenchymal metastases. A retrospective study was performed of breast cancer patients with LM, who received palliative management at Samsung Medical Center between 1995 and 2008. Among the 272 metastatic breast cancer patients with central nervous system (CNS) involvement, 68 patients with LM were identified. The median age was 46 years (range, 24-72 years). The median survival duration from LM to death (LM-OS) was 4.5 months (range, 0.2-26.4 months). Patients surviving for 12 or more months were rarer among triple negative (TN) patients compared to other subtypes (21.7% for HR + ve vs. 27.8% for HER2 + ve vs. 72.7% for TN, P = 0.217). Death caused by CNS involvement appeared to be much more common in TN than in other subtypes (0% for HR + ve vs. 36% for HER2 + ve vs. 64% for TN, P = 0.060). Median survival time from distant metastasis was significantly different among the three groups (28.3 vs. 29.1 vs. 11.8 months, P < 0.0001). However, median survival time from LM did not differ (4.1 vs. 5.9 vs. 3.8 months, P = 0.226). Characteristic manifestations and treatment outcomes of LM may be affected by the unique biology of breast cancer intrinsic subtypes. The different roles of active combined treatment modalities including both systemic chemotherapy and local treatment modalities should be considered to improve outcomes.     

Hypothesized role of pregnancy hormones on HER2+ breast tumor development

Breast cancer incidence rates have declined among older but not younger women; the latter are more likely to be diagnosed with breast cancers carrying a poor prognosis. Epidemiological evidence supports an increase in breast cancer incidence following pregnancy with risk elevated as much as 10 years post-partum. We investigated the association between years since last full-term pregnancy at the time of diagnosis (≤10 or >10 years) and breast tumor subtype in a case series of premenopausal Hispanic women (n = 627). Participants were recruited in the United States, Mexico, and Spain. Cases with known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, with one or more full-term pregnancies ≥1 year prior to diagnosis were eligible for this analysis. Cases were classified into three tumor subtypes according to hormone receptor (HR+ = ER+ and/or PR+; HR? = ER? and PR?) expression and HER2 status: HR+/HER2?, HER2+ (regardless of HR), and triple negative breast cancer. Case-only odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for HER2+ tumors in reference to HR+/HER2? tumors. Participants were pooled in a mixed-effects logistic regression model with years since pregnancy as a fixed effect and study site as a random effect. When compared to HR+/HER2? cases, women with HER2+ tumors were more likely be diagnosed in the post-partum period of ≤10 years (OR = 1.68; 95 % CI, 1.12–2.52). The effect was present across all source populations and independent of the HR status of the HER2+ tumor. Adjusting for age at diagnosis (≤45 or >45 years) did not materially alter our results (OR = 1.78; 95 % CI, 1.08–2.93). These findings support the novel hypothesis that factors associated with the post-partum breast, possibly hormonal, are involved in the development of HER2+ tumors.     

The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer

The detection of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer (MBC) patients is an independent marker of prognosis. This large prospective multicenter study aimed to assess the impact of CTCs on overall survival (OS) and progression free survival (PFS) in patients with predefined molecular subgroups of MBC. To this end, 468 MBC patients were divided into three subgroups based on immunohistochemical staining of the primary tumor: (1) hormone receptor-positive/HER2-negative (HorR+/HER2?), (2) HER2-positive (HER2+), and (3) HorR-negative/HER2-negative (HorR?/HER2?) patients. CTC status (<5 CTCs/7.5 ml blood (CTC-negative) vs. ≥5 CTCs/7.5 ml blood (CTC-positive)) was determined using the CellCearch^® system before patients started a new line of therapy. At baseline, 205 (42 %) patients were CTC-positive. On multivariate analysis, CTC-positivity was an independent prognostic factor for shorter PFS and OS. In HorR+/HER2? patients, median PFS [95 % CI] of CTC-negative versus CTC-positive patients was 8.60 [5.93–11.27] versus 4.33 [3.29–5.38] months (p < 0.001), in HER2+ patients 7.60 [5.40–9.79] versus 6.60 [4.20–9.00] months (p = 0.477) and in HorR?/HER2? patients 5.83 [5.09–6.78] versus 3.05 [1.81–4.29] months (p < 0.001), respectively. Median OS [95 % CI] of CTC-negative versus CTC-positive patients was as follows: not reached by either in the HorR+/HER2? subgroup (p < 0.001), not reached versus 18.07 [11.10–25.05] months (p = 0.001) in the HER2+ subgroup, and not reached versus 8.57 [4.07–13.07] months in the HorR?/HER2? subgroup (p = 0.001). In conclusion, our results strongly confirm the independent prognostic value of CTC enumeration in MBC patients. In contrast to recent reports, there was no association between primary tumor-based molecular subgroups and the impact of CTC status on OS. Hence, CTC status may help to identify patients who require aggressive therapy, especially among those with triple-negative MBC.     

分子分型对乳腺导管内原位癌无复发生存率的影响

目的探讨乳腺导管内原位癌(DCIS)的分子分型与无复发生存率的关系。方法选取南方医科大学附属小榄医院普外科2008年1月至2016年6月收治的DCIS患者135例,根据分子分型分为四个亚组［性激素受体(HR)+／人类表皮生长因子受体2(HER2)-组83例,HR+／HER2+组26例,HR-／HER2+组16例,三阴型(TN)组10例］,比较四组患者的病理分级、肿瘤大小、放疗等临床病理资料及生存预后情况;随访48个月,采用Cox回归分析患者预后的影响因素。结果四组的病理分级和生存状态差异有统计学意义,TN组多为低分化或未分化,未见高分化,且肿瘤复发比例较高(P<005)。四组在生存时间、年龄、肿瘤部位、肿瘤大小、手术方式、有无放疗方面差异无统计学意义;HR+／HER2-组无复发生存率为927％,HR+／HER2+组为923％,HR-／HER2+组为875％,TN组为700％。Cox回归分析结果显示TN亚型是无复发生存率的危险因素(aHR=3538,P=0005),而放疗是无复发生存率的保护因素(aHR=0325,P=0005)。结论分子分型是影响DCIS患者预后的独立危险因素之一,TN型DCIS患者预后较其他亚型差,放疗能改善DCIS患者的无复发生存率。     

Leptomeningeal disease and breast cancer: the importance of tumor subtype

Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. We aimed to characterize clinical features and outcomes of patients with LMD based on BC subtypes. We retrospectively reviewed records of 233 patients diagnosed with LMD from BC between 1997 and 2012. Survival was estimated by the Kaplan–Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Of 190 patients with BC subtype available, 67 (35 %) had hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative BC, 56 (29 %) had HER2+BC, and 67 (35 %) had triple-negative BC (TNBC). Median age at LMD diagnosis was 50 years. Median overall survival (OS) from LMD diagnosis was 4.4 months for HER2+BC (95 % CI 2.8, 6.9), 3.7 months (95 % CI 2.4, 6.0) for HR+/HER2?BC, and 2.2 months (95 % CI 1.5, 3.0) for TNBC (p = 0.0002). Older age was associated with worse outcome (p < 0.0001). Patients with HER2+BC and LMD were more likely to receive systemic therapy (ST) (p = 0.001). Use of intrathecal therapy (IT) (52 %) was similar (p = 0.35). Both IT (p < 0.0001) and ST (p < 0.0001) administration were associated with improved OS. After adjusting for age, IT, extracranial disease, and ST, patients with HER2+BC had better OS compared with HR+/HER2?BC (HR 1.72; 95 %CI 1.07–2.76) and TNBC (HR 3.30; 95 %CI 1.98–5.52). LMD carries a dismal prognosis. Modest survival differences by tumor subtype were seen. Patients with HER2+BC had the best outcome. There is an urgent need to develop effective treatment strategies.