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Keywords:

  • neuroendocrine carcinoma;
  • endocrine carcinoma;
  • invasive carcinoma;
  • ductal carcinoma;
  • breast

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

Neuroendocrine carcinoma (NEC) of the breast, a pathologic entity newly defined in the 2003 World Health Organization classification of tumors, is a rare type of tumor that is not well recognized or studied. The purpose of this first case-controlled study is to reveal the clinicopathologic features, therapeutic response, and outcomes of patients with NEC of the breast.

METHODS:

Seventy-four patients with NEC of the breast who were treated at The University of Texas M. D. Anderson Cancer Center were analyzed; 68 of them had complete clinical follow-up. Two cohorts of invasive mammary carcinoma cases were selected to pair with NEC to reveal demographic, pathologic, and clinical features at presentation, along with therapeutic response to treatment and patient outcomes.

RESULTS:

NEC was more likely to be estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative. Despite similar age and disease stages at presentation, NEC showed a more aggressive course than invasive ductal carcinoma, with a higher propensity for local and distant recurrence and poorer overall survival. High nuclear grade, large tumor size, and regional lymph node metastasis were significant negative prognostic factors for distant recurrence-free survival; high nuclear grade and regional lymph node metastasis were also significant negative prognostic factors for overall survival. Although endocrine therapy and radiation therapy showed a trend toward improved survival, the small number of cases in this study limited the statistical power to reveal therapeutic benefits in NEC of the breast.

CONCLUSIONS:

NEC is a distinct type of aggressive mammary carcinoma. Novel therapeutic approaches should be explored for this uniquely different clinical entity. Cancer 2010. © 2010 American Cancer Society.

Primary neuroendocrine carcinoma (NEC) of the breast is a rare tumor, which was first recognized in 1963,1 and sporadically reported in the literature since then.2-9 However, formal criteria for mammary NEC were not established until 2003, when the World Health Organization (WHO) Classification of Tumors10 defined NEC of the breast as having >50% neoplastic cells expressing neuroendocrine (NE) markers. Because many of the previous studies used varying diagnostic criteria, it is difficult to compare clinicopathologic features and outcome data across these studies.

The WHO estimates that this uncommon and understudied malignancy represents approximately 2% to 5% of breast carcinomas.10 Unlike other special types of breast carcinoma—such as tubular carcinoma (2% of invasive breast carcinomas), invasive cribriform carcinoma (0.5-3.5%), medullary carcinoma (1-7%), and mucinous carcinoma (2%)—the biological behavior of NEC of the breast and its treatment have not been well studied. There are only 5 small series reported using the current WHO criteria, the largest series with follow-up data in only 35 patients.9, 11-14 As a result, the issue of whether NEC of the breast behaves similarly to invasive ductal carcinoma (IDC) not otherwise specified (NOS) and can be treated as IDC remains in question.

In the current paper, we carried out a case control study of the clinicopathologic features in 74 patients with NEC who were treated during the past 5 years at The University of Texas M. D. Anderson Cancer Center (Houston, Tex). These patients presented either with primary disease or with local or distant recurrent disease. Clinical treatment and outcome data were available in 68 of 74 patients with mammary NEC. We show that most NECs are estrogen receptor (ER)/progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER-2) negative, and have a higher tendency for local and distant relapse and poorer overall survival (OS) than IDC NOS. Our results underscore the need to explore novel therapeutic strategies for this aggressive tumor.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Study Group

A total of 74 cases was identified from the Surgical Pathology files at The University of Texas M. D. Anderson Cancer Center that fulfilled the 2003 WHO criteria for NEC of the breast. All cases were confirmed by immunohistochemical staining for NE markers, synaptophysin and/or chromogranin A. The study cases included solid NE carcinoma, atypical carcinoid, and large cell NE carcinoma. A single case of small cell carcinoma of the breast was excluded from the study, as the clinicopathologic features and poor clinical outcome of small cell carcinoma have been well documented.15, 16 Medical records were retrospectively reviewed to obtain demographics, clinicopathologic factors, treatments, and outcome information.

Each patient was carefully staged to rule out breast metastasis of NEC from other organs such as the gastrointestinal tract or lung (5 such patients were identified during the past 5 years, and were excluded from the current study). In addition, pathologic review of hormone receptor expression and the presence of in situ carcinoma were used to verify that the tumors were primary to the breast.

All 74 patients with NEC were treated at The University of Texas M. D. Anderson Cancer Center for primary or recurrent disease during the past 5 years. However, some of the patients were initially diagnosed with breast carcinoma and treated at other institutions before their presentation at our institution. Dates of breast cancer diagnoses ranged from January 1984 to August 2008. Two (3%) patients were first diagnosed with breast cancer in the 1980s, 3 (4%) in the 1990s, and the remaining 69 (93%) in or after 2000. The diagnoses of NEC in patients who presented before the WHO guidelines of 2003 were retrospectively rendered based on pathologic review of their materials. Regardless of their initial classification, all patients were treated as invasive mammary carcinoma NOS, the same as our control group for clinical outcome.

The institutional review board at The University of Texas M. D. Anderson Cancer Center approved the study and waived the need to obtain informed consent from each patient.

Control Group for Clinical Presentation

A total of 5165 consecutive newly diagnosed breast cancer patients treated in the Nellie B. Connally Breast Center at The University of Texas M. D. Anderson Cancer Center between January 2004 and February 2008 were identified from the Breast Cancer Management System Database and were used as a control cohort to compare features at clinic presentation with the NEC study group. We refer to them in the following text as the presenting control cohort.

As The University of Texas M. D. Anderson Cancer Center is a tertiary cancer center and a major referral hospital, the clinical presentation of our patients might not be generalizable to the overall population with invasive mammary carcinoma. Therefore, we also used Surveillance, Epidemiology, and End Results (SEER) data released in May 2009 for comparison.17 The SEER database includes data from 18 population-based registries that cover approximately 26% of US patients. Patients with stage I to IV invasive mammary carcinoma diagnosed between 2004 and 2006 were identified from SEER (n = 139,875) to compare with our NEC study cohort. We chose the 2004-2006 time frame from the SEER database because these patients were staged according to the American Joint Committee on Cancer (AJCC) sixth edition, which was used for the comparison between the 2 different cohorts.

Case-Control Group for Clinical Outcome

A cohort of 142 control cases with IDC NOS was randomly identified from the Surgical Oncology database and Surgical Pathology files to match the sex, ethnicity, age (±3 years), pathologic stage, HER-2/neu status, and surgical procedure (partial vs total mastectomy) with 63 NEC study cases. The M. D. Anderson Surgical Oncology database has been collecting patient data prospectively since 2000 and accrues approximately 1500 patients per year. The Surgical Pathology database overlaps with the Surgical Oncology database, but with more detailed pathologic information. Despite thorough searches of the 2 databases, 11 of 74 NEC patients could not be included in the matched follow-up studies (1 because of unknown lymph node status and 10, including 6 stage IV patients, for whom we could not identify controls in our databases that exactly matched all 6 clinicopathologic parameters as indicated above).

The 142 primary invasive carcinomas of the IDC NOS cohort were initially diagnosed between April 1989 and May 2006. One (0.7%) patient was diagnosed in the 1980s, 20 (14%) in the 1990s, and the remaining 121 (85%) in or after 2000.

Histopathologic Examination

The histopathology of each case was re-reviewed and the diagnoses were confirmed by positive immunohistochemical staining for synaptophysin (syn88, BioGenex Laboratories, San Ramon, Calif) and/or chromogranin A (PHE5, Chemicon International, Rancho California, Calif) in >50% of the invasive tumor cells. Immunohistochemistry was performed on 4-μm sections using a Dako autostainer (Dako, Carpinteria, Calif) with the LSAB-2 peroxidase kit (Dako), with 3,3′ diaminobenzidine used as the chromogen. ER/PR/HER-2 results were obtained from the original pathology reports. Nuclear staining in ≥10% of tumor cells was the threshold for ER and PR positivity. Interpretations of HER-2 immunohistochemical staining and fluorescence in situ hybridization analysis were based on the most recent American Society of Clinical Oncology/College of American Pathologists guidelines.18 All ER/PR/HER-2 results were expressed quantitatively in the original pathology reports, so that the data can be extracted and interpreted based on current guidelines for this study. The same methods and scoring system were used in NEC and IDC groups.

Statistical Analysis

Descriptive statistics were calculated for demographic and clinicopathologic factors, and differences in these between NEC of the breast and IDC NOS were compared using chi-square or Fisher exact test, where appropriate.

Survival data were analyzed based on 3 endpoints from the time of diagnosis. Local recurrence-free survival (LRFS) was defined as the time to local disease recurrence or death as a result of NEC or IDC NOS. Distant recurrence-free survival (DRFS) was defined as the time to distant disease recurrence or death from NEC or IDC NOS. OS was defined as the time to death from the date of diagnosis.

Unadjusted survival probabilities of LRFS, DRFS, and OS were estimated using Kaplan-Meier analysis on matched patient cohorts. Unadjusted intergroup comparisons based on each outcome were made using the log-rank test. Associations between clinicopathologic factors and clinical outcomes were estimated using the Cox proportional hazards regression model. All calculations were performed with Stata software (Stata/SE 9.0 for Windows; StataCorp, College Station, Tex). Two-tailed P values ≤.05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Clinical Presentation at Diagnosis

The clinicopathologic characteristics of the 74 patients with NEC of the breast at presentation and the presenting control cohort of 5165 patients from The University of Texas M. D. Anderson Cancer Center and 139,875 patients from the SEER database are summarized in Tables 1 and 2.

Table 1. Demographic and Clinicopathologic Features of the NEC Cohort (n = 74) Compared With the Invasive Mammary Carcinoma (n = 5165) Control Cohort at Clinical Presentationa
FeaturesNEC Cohort, n = 74Invasive Mammary Carcinoma Cohort, n = 5165P
  • NEC indicates neuroendocrine carcinoma; SD, standard deviation; NS, not significant; AJCC, American Joint Committee on Cancer; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2.

  • a

    Statistical analysis excludes unknown cases.

Age, mean y ± SD61.2 ± 12.453.9 ± 12.2<.0001
Tumor size, mean cm ± SD2.70 ± 2.062.20 ± 2.13.04
 No. of Patients%No. of Patients% 
Sex    NS
 Women7297.3512799.3 
 Men22.7380.7 
Race    NS
 Caucasian5979.73353868.50 
 Hispanic810.8171813.90 
 African American56.7664912.57 
 Other11.352605.03 
 Unknown11.3500 
Menopausal status    .007
 Premenopausal1114.86170633.03 
 Perimenopausal11.351733.35 
 Postmenopausal5371.62322962.52 
 Unknown912.16571.10 
AJCC TNM stage    NS
 I2534.25179834.81 
 II2939.73211841.01 
 III1317.81109521.20 
 IV68.221542.98 
ER    <.0001
 Positive (≥10%)6891.89369671.56 
 Low positive (1-9%)22.702084.03 
 Negative (0%)34.05119723.18 
 Unknown11.35641.24 
PR    .036
 Positive (≥10%)5168.92295057.12 
 Low positive (1-9%)810.814308.33 
 Negative (0%)1418.92170032.91 
 Unknown11.35851.65 
HER-2    <.0001
 Positive22.7079115.31 
 Negative6790.54407778.94 
 Equivocal11.35721.39 
 Unknown45.412254.36 
Nuclear grade    <.0001
 122.704388.48 
 25777.03204539.59 
 31520.27257649.87 
 Unknown001062.05 
Table 2. Demographic and Clinicopathologic Features of the NEC Cohort (n = 74) Compared With the Invasive Mammary Carcinoma Patients From the SEER Cohort (2004-2006) (n = 139,875) at Clinical Presentationa
FeaturesNEC Cohort, n = 74Invasive Mammary Carcinoma From SEER Cohort, n = 139,875P
  • NEC indicates neuroendocrine carcinoma; SEER, Surveillance, Epidemiology, and End Results; SD, standard deviation; NS, not significant; AJCC, American Joint Committee on Cancer; ER, estrogen receptor; PR, progesterone receptor.

  • a

    Statistical analysis excludes unknown cases.

Age, mean y ± SD61.2 ± 12.461.0 ± 14.1NS
Tumor size, mean cm± SD2.70 ± 2.062.26 ± 2.21.002
 No. of Patients%No. of Patients% 
Sex    NS
 Women7297.3138,81899.2 
 Men22.710570.8 
Race    NS
 Caucasian5979.73103,41773.9 
 Hispanic810.8112,8489.2 
 African American56.7612,6269.0 
 Other11.3510,4667.5 
 Unknown11.355220.4 
AJCC TNM stage    NS
 I2534.2567,09848.0 
 II2939.7348,20034.5 
 III1317.8117,17112.3 
 IV68.2274065.3 
ER    <.001
 Positive7094.59100,43071.8 
 Negative34.0528,54620.4 
 Unknown11.3510,8997.8 
PR    <.001
 Positive5979.7383,21959.5 
 Negative1418.9243,39731.0 
 Unknown11.3513,2599.5 

Sex and Ethnicity

Most patients with NEC of the breast were women (72 of 74, 97%) similar to controls (5127 of 5165, 99%). Fifty-nine (80%) were Caucasian, 5 (7%) African American, 8 (11%) Hispanic, 1 (1%) Asian, and 1 (1%) unknown. Compared with the control cohort from The University of Texas M. D. Anderson Cancer Center and SEER, no differences were observed in the proportions of different ethnic groups.

Age at Diagnosis

The mean age of patients with NEC at diagnosis was 61 years (range, 29-82 years; median, 63 years). NEC patients were significantly older (P < .0001) than the presenting control cohort of 5165 patients (mean, 54 ± 12 years) from our hospital, but there was no difference from the general mammary carcinoma patients (mean, 61 ± 14 years) from the SEER database.

Menstrual Status

The majority of patients with NEC of the breast were postmenopausal (53 of 74, 72%), 11 (15%) were premenopausal, 1 (1%) was perimenopausal, and 9 (12%) were of unknown menopausal status. There were significantly more postmenopausal NEC patients as compared with the control cohort from our hospital (P = .007). This result was consistent with the higher presenting age at diagnosis in NEC patients. No menstrual status in the SEER database was available for comparison.

Stage at Diagnosis

Tumor stage (T classification)

In NEC of the breast, maximum tumor diameters ranged from 0.8 to 13.5 cm (median, 2.2 cm; mean, 2.7 cm). Thirty-three (45%) were stage T1 (≤2 cm), 31 (42%) were T2 (>2–5 cm), 4 (5%) were T3 (>5 cm), and 6 (8%) were T4 (skin or chest wall involvement). Tumor size in NEC was larger than the tumor sizes of both the presenting control cohort from our hospital and the SEER database (P = .04 and .002, respectively) (Tables 1 and 2). However, there was no significant difference in T stage between NEC patients and the presenting control cohort (Table 1).

Regional lymph node metastasis (N classification)

Forty-one (57%) NEC patients presented with no regional lymph node metastasis (N0), 31 (42%) with lymph node metastasis (N1, 2, or 3), and 2 (3%) with unknown lymph node status (both T2 cases). Regional lymph node metastasis was associated with higher tumor stage, being present in 7 (21%) of 33 T1 tumors, 16 (55%) of 29 T2 tumors, 3 (75%) of 4 T3 tumors, and 5 (83%) of 6 T4 tumors. The proportions of N0:N1:N2:N3 stages did not differ between NEC and the presenting control cohort (data not shown).

Distant metastasis (M classification)

Six (8%) NEC patients presented with stage IV disease with distant metastases.

TNM stage

On the basis of the AJCC staging system (version 6),19 25 (34%) NEC patients were stage I, 29 (39%) stage II (IIA, 17 of 74, 23%; IIB, 12 of 74, 16%), 13 (18%) stage III (IIIA, 7 of 74, 9%; IIIB, 5 of 74, 7%; IIIC, 1 of 74, 1%), and 6 (8%) stage IV at presentation. TNM stage was unknown in the remaining 1 (1%) patient. There were no significant differences in TNM stages between NEC patients and the presenting control cohort from our hospital or the SEER database (Tables 1 and 2).

Tumor Grade

In The University of Texas M. D. Anderson Cancer Center, breast cancer was graded by the Modified Black's Nuclear Grading Scheme. Most NEC were grade 2 tumors (57 of 74, 77%), with fewer grade 3 (15 of 74, 20%) and grade 1 (2 of 74, 3%) tumors. There were significantly more grade 2 tumors in NEC as compared with the presenting control cohort (P<.0001) (Table 1). However, differences in the proportions of grade 1 and grade 3 tumors between NEC and the control cohort did not reach statistical significance (data not shown). Nuclear grade status is not available in the SEER database for comparison.

Receptor Status

Most NECs of the breast were ER/PR positive and HER-2 negative. Sixty-eight (92%) were ER positive, and 51 (69%) were PR positive. ER/PR expression was significantly higher than in the presenting control cohort from our hospital (P < .0001 and P = .036, respectively) (Table 1) and from the SEER database (P < .001 and P < .001, respectively) (Table 2). Sixty-seven (91%) NEC patients were HER-2 negative; only 2 (3%) were HER-2 positive, 1 (1%) was equivocal, and 4 (5%) had unknown HER-2 status. HER-2 overexpression in patients with NEC was significantly lower than that in the presenting control cohort (P < .0001) from our hospital (Table 1). HER-2 status is not available from the SEER database for comparison.

Clinical Outcomes

The median follow-up for patients with NEC of the breast was 29 months (range, 2-260 months). Six patients were lost to follow-up after variable times (from 2 to 23 months). Eleven (15%) of 74, including 2 stage IV patients, died of disease at 25 to 260 months after the initial diagnosis. The median follow-up for our matched control cohort with stage I to III disease was 67 months (range, 9-215 months). Eight (5.6%) of 142 of the control cohort died of disease at 23 to 91 months after the initial diagnosis.

Local recurrence

NEC patients with stage I to III disease had a higher rate of local recurrence (7 of 67, 10%) than the matched IDC NOS cohort (4 of 142, 3%). Log-rank test revealed statistical significance between these 2 groups (P = .001) (Fig. 1). Kaplan-Meier analysis revealed a 15% risk for local recurrence by 5 years, with a median local recurrence-free time of 177 months in patients with NEC.

thumbnail image

Figure 1. Overall survival, distant recurrence-free survival, and local recurrence-free survival comparisons between 63 patients with stage I to III neuroendocrine carcinoma (NEC) and 142 strictly matched controls with invasive ductal carcinoma (IDC) not otherwise specified are shown.

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Distant recurrence

Distant recurrence rate was also much higher (15 of 67, 22%) in stage I to III NEC patients than it was in the matched IDC NOS cohort (5 of 142, 4%). Log-rank test demonstrated statistical significance between these 2 groups (P < .0001) (Fig. 1). Kaplan-Meier analysis revealed a 34% risk for distant recurrence within 5 years, with a median distant recurrence-free time of 73 months among NEC patients. The most common distant recurrence sites were bone and liver; other sites included lungs, brain, pleura, mediastinal lymph nodes, adrenal glands, ovaries, fallopian tubes, colon, ileum, and pancreas.

Survival

Three sets of survival data (LRFS, DRFS, and OS) were analyzed using our matched IDC NOS group. We identified 142 IDC NOS patients that strictly matched 63 patients with NEC of the breast in age (±3 years), ethnicity, pathologic stage, surgical procedure, and HER-2 status, with a ratio of 1:4 controls to each study case. Eleven (including 6 stage IV) NEC cases had no strictly matched controls identified, and therefore the study was performed only on the 63 known stage I to III cases. Kaplan-Meier analysis revealed that patients with NEC of the breast had significantly worse clinical outcomes for LRFS, DRFS, and OS than IDC NOS patients (P = .001, P < .0001, and P = .002, respectively) (Fig. 1).

Clinical Management

All of our NEC patients received therapy as conventional breast cancers. Of 74 patients, 60 with stage I to III disease completed treatment and had available clinical outcomes at the time of data analysis (Fig. 2). Kaplan-Meier analysis was performed to correlate therapeutic intervention with outcome (Table 3). Patients who received endocrine therapy had longer OS (median, 156 vs 50 months) and DRFS (median, 138 vs 53 months) than those who did not receive it. Patients who received radiotherapy had longer OS (median, 156 vs 88 months) and DRFS (median, 138 vs 80 months) than those who did not receive it. In contrast, patients given chemotherapy had both shorter OS (median, 88 vs 260 months) and DRFS (median, 62 vs 138 months) than patients without chemotherapy. However, none of these differences reached statistical significance, most likely because of small patient numbers and lack of statistical power. In addition, there was no combination of 2 or 3 therapies that reached statistical benefit (data not shown).

thumbnail image

Figure 2. Treatment and outcome information for 60 patients with neuroendocrine carcinoma (NEC) is shown. The data indicate a high mortality rate in patients who developed distant recurrence (DR) compared with those with no disease recurrence or local recurrence (LR) only. H indicates endocrine therapy; C, chemotherapy; XRT, radiotherapy; LR + DR, LR followed by DR; NED, no evidence of disease; AWD, alive with disease; Mets, metastases; DOD, dead of disease.

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Table 3. OS and DRFS of Patients With NEC of the Breast
 5-Year OSMedian OS, moP5-Year DRFSMedian DRFS, moP
No. of Patients at RiskSurvival Rate, %No. of Patients at RiskSurvival Rate, %
  1. OS indicates overall survival; DRFS, distant recurrence-free survival; NEC, neuroendocrine carcinoma; NS, not significant; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2.

Age, y   NS   NS
 ≤601284156 96263 
 >60883 66673 
Race   NS   NS
 Caucasian1681156 126066 
 Non-Caucasian4100 393 
Menopausal status   NS   NS
 Premenopausal6100156 47766 
 Postmenopausal1080260 86173 
T classification   NS   .0206
 T110100260 874 
 T296748 65562 
 T31 128 
 T4210093 210066 
N classification   .0219   .0192
 N01689260 127680 
 N1, 2, 357588 34453 
Nuclear grade   .0003   .005
 1, 21691156 137073 
 333848 22733 
TNM stage   .0335   .0027
 I8100260 786 
 II107588 66062 
 III1 153 
 IV36793 35019 
ER   NS   NS
 Positive1886156 146967 
 Negative250 1 
PR   NS   NS
 Positive1275156 106467 
 Negative810088 66973 
HER-2   NS   NS
 Positive2100 167 
 Negative168293 136733 
Surgical procedure   NS   NS
 Mastectomy118693 97773 
 Partial mastectomy887 55362 
Endocrine therapy   NS   NS
 No23350 22753 
 Yes1790156 1180138 
Chemotherapy   NS   NS
 No7100260 795138 
 Yes107888 85862 
Radiotherapy   NS   NS
 No76888 56780 
 Yes1291156 972138 

Prognostic Factors

Analyses of prognostic factors are summarized in Table 3. Univariate analysis (Kaplan-Meier) showed that higher nuclear grade, higher tumor stage, and regional lymph node metastasis were inversely associated with DRFS (P = .005, .02, and .02, respectively); higher nuclear grade and regional lymph node metastasis were also inversely correlated with OS (P = .0003 and .02, respectively). In multivariate analysis, T stage was no longer significant in predicting OS and DRFS (data not shown); lymph node metastasis was a significant negative prognostic factor for DRFS (P = .01) and was borderline significant for OS (P = .055).

The development of distant recurrence was a significant predictor of poor OS (P < .0001) (data not shown). Median OS was 88 months in stage I to III NEC patients who developed distant recurrence, and their 5-year OS rate was only 72%, as compared with 100% in NEC patients without distant recurrence. The 2-year and 5-year survival rates after distant recurrence were 38% and 28%, respectively. The median survival time after distant recurrence was only 18 months in these patients.

In the case control study, NEC was significantly worse in OS, DRFS, and LRFS than IDC NOS when patients were matched with age, ethnicity, pathologic stage, HER-2/neu status, and surgical procedure. Because of the presence of other variables, including nuclear grade and ER and PR status, we pooled the NEC and IDC NOS control cases, stratified the data based on the matched factors, and performed multivariate analysis on the unmatched variables using Cox proportional hazard model analysis.20 Analysis results indicated that NE differentiation was a significant and independent predictor of poor OS, DRFS, and LRFS (Table 4). In the same analysis, high nuclear grade was shown to be a significant predictor of poor OS and DRFS but not LRFS.

Table 4. Multivariate Analysis of Prognostic Factors for OS, DRFS, and LRFS of NEC and IDC Patientsa
FactorsOSDRFSLRFS
HR95% CIPHR95% CIPHR95% CIP
  • OS indicates overall survival; DRFS, distant recurrence-free survival; LRFS, local recurrence-free survival; NEC indicates neuroendocrine carcinoma; IDC, invasive ductal carcinoma; HR, hazard ratio; CI, confidence interval; NS, not significant; ER, estrogen receptor; PR, progesterone receptor.

  • a

    Results were obtained using a Cox proportional hazard model, stratified by age group (≤60 years old or not), race (Caucasian or not), TNM stage (I, II, and III), and the above 4 independent variables.

Nuclear grade 1, 2 vs 3.03.004-.23.0007.06.009-.40.004.81.17-3.83NS
ER status, positive vs negative2.90.50-16.74NS2.42.44-13.28NS1.31.11-14.94NS
PR status, positive vs negative.81.22-2.99NS1.04.36-3.04NS2.42.45-13.00NS
Neuroendocrine differentiation, positive vs negative24.384.02-147.87.000551.228.92-294.27<.00016.641.67-26.36.007

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Our study is the largest series of NEC of the breast to date, and the only 1 to use paired control cases of IDC to reveal the clinicopathologic features and prognostic significance of NE differentiation. Although NEC of the breast was recognized >40 years ago, this entity was first clearly defined in the most recent WHO classification of tumors10 in 2003. The new WHO criteria define this type of tumor as >50% of the neoplastic cells expressing NE markers, a definition that was based on the 2001 study by Sapino et al.9 This criterion distinguishes NEC of the breast from other mammary carcinomas that show only NE morphological features or focal (ie, <50%) NE differentiation. The importance of this definition is highlighted by 2 studies that showed that focal NE differentiation had no prognostic significance as compared with breast carcinoma NOS.8, 21 Because NEC is an uncommon and newly defined entity, to date there have been only 5 series reported9, 11-14 using this diagnostic criteria. None of those series was case controlled, all had relatively small numbers of patients, and they reached conflicting conclusions about the significance of NEC. Three studies with 13, 12, and 7 patients, respectively, showed better prognosis in NEC.11, 12, 14 Two studies with 35 and 10 patients showed no prognostic significance.9, 13

Our data show that NEC is a distinct subtype of mammary carcinoma. NECs are significantly more likely to be ER/PR positive and HER-2 negative. Although these women do not present at older ages or with higher stage disease as compared with patients with invasive ductal carcinoma, their clinical outcomes are poorer and they have a higher tendency for local and distant recurrence. Thus, our findings support the observations of the earlier studies regarding ER+/PR+/HER-2 status of NEC, but conflict with the earlier conclusions about its older age at presentation and its prognostic significance. The larger number of patients in our series and our strict case controls might account for these differences.

NEC of the breast comprises several different histologic types. Solid papillary variant is mainly considered as an in situ carcinoma, which can be associated with invasive carcinoma. Previous studies have suggested that cellular mucinous and solid papillary types of NEC are associated with a better prognosis.9, 22 In the current study, there were only 3 cellular mucinous carcinomas and no cases of solid papillary carcinoma. Our study shows a worse prognosis for NEC of the breast as compared with previous studies with large proportions of solid papillary and/or mucinous carcinomas. Therefore, the current study indicates that invasive NEC other than mucinous carcinoma or solid papillary carcinoma carries a worse prognosis.

Our study also analyzed the clinical prognostic factors in NEC of the breast. Regional lymph node metastasis was significantly and independently associated with poor distant recurrence-free survival by multivariate analysis. Regional lymph node metastasis also showed a trend in predicting poor overall survival (P = .055). In addition, high nuclear grade was a poor prognostic predictor for both DRFS and OS.

As most of our patients with NEC were ER/PR positive and HER-2 negative, we reviewed the clinical treatment of these patients to investigate whether endocrine therapy provided survival benefit as compared with chemotherapy or radiation therapy. Although the mean overall survival time was longer in hormonally treated patients than in untreated patients (156 vs 50 months), this did not reach statistical significance, probably because of the small number of ER/PR negative cases. Neither chemotherapy nor radiation therapy reached statistical significance in survival benefit either (standard chemotherapy actually showed a trend toward poorer OS and DRFS). In addition, there was no combination of 2 or 3 therapies that appeared superior to others. Several possible interpretations exist for these data. First, it could be hypothesized that NEC of the breast is similar to NEC of other sites such as the gastrointestinal tract and lungs, which tend to be resistant to multiple therapeutic interventions, including chemotherapy.23 A second possibility is that the therapeutic effects of endocrine therapy, chemotherapy, and radiation therapy were not revealed in our study because of the small number of cases and limited follow-up times in some of our patients. Lack of statistical power because of the small case numbers is a limitation of the current study. Therefore, additional studies with longer follow-up and more cases need to be further pursued. Third, NEC of the breast may be biologically distinct from other types of breast cancers, and current treatments for breast cancer are not best suited for NEC. Indeed, a recent study by Weigelt et al has shown that cellular mucinous carcinomas—a variant of NEC of the breast—have a distinct molecular signature as compared with IDC NOS.24

In summary, the results of this case-controlled study of 74 NECs of the breast demonstrate that NEC is a subtype of mammary carcinoma with several distinctive features. In comparison to the usual invasive ductal carcinomas, NECs are more likely to be ER/PR positive and HER-2 negative. Despite similar age and disease stages at presentation, NEC shows a more aggressive course than ductal carcinoma, with a higher propensity for local and distant recurrence and poorer OS. Finally, endocrine therapy and radiation therapy showed trends in survival benefit—whereas standard chemotherapy was associated with poorer outcome—but no type of treatment reached statistical significance in the current study. Additional studies with longer follow-up and greater case numbers will be needed to address this issue. However, the results of this study suggest that novel therapeutic interventions—particularly medications such as antiangiogenesis agents that are used for NEC in other sites—should be explored.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The authors gratefully acknowledge Ms. Limin Hsu for her help in obtaining the data on the control population, Ms. Kim-Anh Vu for graphic assistance, Ms. Kristi Speights for editing the article, and Dr. Michael Gilcrease for his instructive review and discussion of the article.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported in part by Research Start-up Funds from The University of Texas M. D. Anderson Cancer Center (Y. Wu) and the 100 Talents Program from the School of Medicine, Shanghai Jiao Tong University and Chinese Nature Science Foundation (grant 30672328; Z. Tian).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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