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Keywords:

  • breast carcinoma;
  • age;
  • prognosis;
  • disease;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The purpose of the current study was to describe a population of young patients with breast carcinoma, their characteristics at the time of diagnosis, and the association of these characteristics with disease recurrence and survival.

METHODS

Four hundred fifty-two women age ≤ 35 years with breast carcinoma were registered at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1990 and 2002. The relation between clinicopathologic factors and disease recurrence-free survival (RFS) and overall survival (OS) was assessed. Cox regression analysis was used to identify independent survival predictors.

RESULTS

The median age of the patients was 32 years. Most of the patients were white, and 20% were obese. Approximately 50% reported oral contraceptive use, 34% reported a family history of breast carcinoma, and 5% reported a family history of ovarian carcinoma. Sixty-nine percent of tumors were nuclear Grade 3 (using the modified Black's nuclear grading system), 52% had positive estrogen receptors, and 48% had positive progesterone receptors. HER-2/neu status was available in 60% of tumor specimens and 34% were HER-2/neu positive. The median follow-up was 36 months. There were 185 disease recurrences and 84 deaths. RFS was significantly shorter in patients who reported a family history of ovarian carcinoma (P < 0.0001) and in those who had hormone receptor-negative tumor specimens (P = 0.001). OS was significantly shorter in patients who reported a family history of ovarian carcinoma (P = 0.001), those who had hormone receptor-negative tumor specimens (P < 0.0001), or those with > nuclear Grade 3 tumor specimens (P = 0.005).

CONCLUSIONS

This young population with breast carcinoma was found to have more aggressive biologic features. Hormone receptor negativity and a family history of ovarian carcinoma were associated with shorter RFS and OS. Cancer 2005. © 2005 American Cancer Society.

Breast carcinoma is the leading cancer diagnosis and the second cause of cancer death among women in the U.S.. Although most breast carcinomas occur in postmenopausal women, approximately 2% of patients with breast carcinoma are age ≤ 35 years old at the time of diagnosis.1, 2 Breast carcinoma in young patients has been reported to present with more aggressive biologic characteristics and to behave poorly compared with the disease in older patients.3–6 Several population studies have related age at the time of diagnosis to risk of death, showing the youngest and the very oldest at higher risk of death.3–6 The Experts' Consensus of the St. Gallen Conference in 1998 concluded that age < 35 was a poor prognostic factor7 and supported the use of more aggressive systemic therapy, including chemotherapy in all younger patients regardless of other tumor or host factors. However, to our knowledge most of the data on biologic characteristics and treatment to evaluate these patients derive from older cohort studies using different staging procedures, laboratory assays, and treatment approaches.

The goals of the current study are to describe this population of young patients with breast carcinoma of age ≤ 35 years in terms of clinical characteristics at the time of diagnosis and treatments received, and to assess factors possibly associated with disease recurrence and overall survival (OS).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The database of the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center (UTMDACC) was searched to identify patients with breast carcinoma who were age ≤ 35 years at the time of diagnosis between 1990 and 2002. The institutional review board of UTMDACC approved the retrospective review of the medical records for the purposes of the current study.

Breast carcinoma diagnosis was made by core-needle or excisional biopsy of the breast tumor. All pathologic specimens were reviewed by the breast pathologists at UTMDACC. The histologic type of all tumor specimens was defined according to the World Health Organization's classification system.8 The histologic grade was defined according to the modified Black's nuclear grading system.9 Immunohistochemical analysis to determine estrogen (ER) and progesterone receptor (PR) status was performed using standard procedures on 4-μm sections of paraffin-embedded tissue specimens stained with the monoclonal antibodies 6F11 and 1A6 (Novacastra Laboratories Ltd., Burlingame, CA) for ER and PR, respectively. Nuclear staining > 10% was considered a positive result. Before 1993, the dextran-coated charcoal ligand-binding method was used to determine ER and/or PR status. HER-2/neu gene amplification was done by fluorescence in situ hybridization analysis of breast tumor specimens using the PathVysion HER-2/neu DNA probe kit (Vysis, Inc., Downers Grove, IL) according to the manufacturer's instructions. A tumor specimen with a ratio > 2.0 was considered amplified. Signals were counted for 60 tumor nuclei within areas of invasive carcinoma. Ductal epithelial cells served as an internal control.10

All patients received anthracycline-based chemotherapy with 4–6 cycles of 5-fluorouracil at a dose of 500 mg/m2 given intravenously (i.v.) on Days 1 and 4, doxorubicin at a dose of 50 mg/m2 i.v. by continuous infusion over 72 hours on Days 1–3, and cyclophosphamide at a dose of 500 mg/m2 i.v. on Day 1. One hundred fifty-nine (35%) patients received additional taxanes in the neoadjuvant or adjuvant setting, either weekly paclitaxel (at a dose of 175–250 mg/m2 i.v. on Day 1, which was reduced to 80 mg/m2 i.v. on Day 1 every week for 12 weeks) or docetaxel (at a dose of 75–100 mg/m2 on Day 1 every 3 weeks for 4 cycles). Breast surgery consisted of total mastectomy (n = 214) or segmental mastectomy (n = 127) when permitted by tumor size according to the judgment of the multidisciplinary care team. Axillary lymph node dissection had been performed in 338 (75%) patients. For patients receiving neoadjuvant chemotherapy, a pathologic complete response was defined as no evidence of invasive carcinoma in the breast and the axillary lymph nodes at the time of surgery. Forty-seven percent of the patients with hormone receptor-positive tumor specimens received tamoxifen at a dose of 20 mg daily for 5 years. Radiotherapy was delivered to patients who received breast conservation and patients with larger tumors and four or more positive lymph nodes at the time of surgery.

Information for family history and oral contraceptive use was self-reported by patients and collected from the medical record. Family history of ovarian and/or breast carcinoma was considered positive, if any first or second-degree relative of the patient had either primary breast or ovarian carcinoma.

The characteristics of this patient population at the time of diagnosis were described by tabulation of categoric variables. Continuous variables were described by their minimum, median, and maximum. The treatments received by this population were summarized by cross-tabulation of treatment type with whether the patient had received neoadjuvant chemotherapy. Disease characteristics that were measured at the time of surgery were summarized by cross-tabulation with whether the patient had received neoadjuvant chemotherapy. The Kaplan–Meier product-limit method was used to describe disease recurrence-free survival (RFS) and OS among the entire patient population, as well as by patient and disease characteristics. The number of months of RFS was measured from the date of diagnosis to the date of disease recurrence or last follow-up. The number of months of OS was measured from the date of diagnosis to the date of death or last follow-up.

The log-rank statistic was used to test for differences in RFS (Fig. 1) and OS (Fig. 2) between groups. Cox proportional hazards models were also used to assess the associations between survival and patient characteristics at the time of diagnosis, including obesity, race, oral contraceptive use, family history of breast carcinoma, family history of ovarian carcinoma, and nuclear grade. HER-2/neu status was excluded because of the large amount of missing data associated with this variable, and hormone receptor status was excluded because it was found to violate the assumption of the Cox proportional hazards model. Tests for all pair-wise interactions were done, but none was found to be significant. One hundred fourteen statistical tests were performed and therefore, using the Bonferroni correction, only Ps < 0.0004 should be considered statistically significant.

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Figure 1. Disease recurrence-free survival by family history of ovarian carcinoma.

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Figure 2. Overall survival by family history of ovarian carcinoma.

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Statistical analyses were performed using SAS software, version 8 (SAS Institute Inc., Cary NC) and S-Plus 6.1 (Insightful Corporation, Seattle, WA) software.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Four hundred fifty-two patients with breast carcinoma age ≤ 35 years were diagnosed and treated at UTMDACC between 1990 and 2002. The median follow-up time was 36 months (range, 1–161 months).

Table 1 summarizes this population's characteristics. The median age at diagnosis was 32 years. Most patients had a body mass index (BMI) < 30, were white, and reported no family history of breast or ovarian carcinoma. Approximately 50% of the patients reported some use of oral contraceptives. The majority of patients presented with Black's nuclear Grade 3 disease, were HER-2/neu negative, and had ER/PR-positive disease.

Table 1. Patient Characteristics at at the Time of Diagnosis
CharacteristicsNo. of patients (%)
  1. BMI: body mass index; ER: estrogen receptor; PR: progesterone receptor.

Median age at diagnosis (yrs) (range)32 (17–35)
Obesity 
 BMI < 30331 (79.76)
 BMI ≥ 3084 (20.24)
Race 
 White297 (65.71)
 Black43 (9.51)
 Hispanic85 (18.81)
 Asian18 (3.98)
 Other9 (1.99)
Menopausal status 
 Pre-menopausal399 (93.66)
 Postmenopausal (surgery)27 (3.34)
Oral contraception 
 Yes233 (51.55)
 No219 (48.45)
Family history of breast carcinoma 
 None298 (65.93)
 1st-degree relative27 (5.97)
 2nd-degree relative114 (25.22)
 1st and 2nd degree relative13 (2.88)
Family history of ovarian carcinoma 
 None429 (94.91)
 1st-degree relative6 (1.33)
 2nd-degree relative17 (3.76)
 1st- and 2nd-degree relative0 (0.00)
Nuclear grade 
 111 (2.72)
 2113 (27.90)
 3281 (69.38)
ER 
 Positive205 (52.30)
 Negative187 (47.70)
PR 
 Positive183 (47.53)
 Negative202 (52.47)
ER and PR 
 Either positive241 (61.64)
 Both negative150 (38.36)
HER-2/neu 
 Positive92 (33.70)
 Negative181 (66.30)

Table 2 summarizes this population's treatment and disease characteristics at the time of surgery stratified by neoadjuvant chemotherapy. Seventy-three percent of these patients did not receive neoadjuvant chemotherapy. Among these patients, 71% received surgery and 61% of the surgical procedures were mastectomies. At the time of surgery, 63% of patients had AJCC (2003) Stage II–IIIA disease. The majority of these patients received adjuvant chemotherapy (74%) but did not receive taxane or tamoxifen, and 50% received radiotherapy.

Table 2. Treatments and Disease Characteristics at the Time of Surgery
CharacteristicsAdjuvant chemotherapyNeoadjuvant chemotherapy
No. of patients (%)No. of patients (%)
No. of patients329123
Tumor size  
 < 2117 (43.7)70 (68.6)
 2–5135 (50.4)24 (23.5)
 > 516 (6)8 (7.8)
No. of positive lymph nodes  
 0–3232 (76.3)84 (68.9)
 4–1051 (16.8)25 (20.5)
 > 1021 (6.9)13 (10.7)
Overall stage  
 00 (0)14 (11.7)
 I84 (29.7)13 (10.8)
 II–IIIA178 (62.9)77 (64.2)
 IIIB-inflammatory6 (2.1)10 (8.3)
 IV13 (4.6)4 (3.3)
 X2 (0.7)2 (1.7)
Taxane  
 No261 (79.3)32 (26)
 Yes68 (20.7)91 (74)
Tamoxifen  
 No236 (71.7)72 (58.5)
 Yes93 (28.3)51 (41.5)
Surgery type  
 Lumpectomy91 (38.7)36 (34)
 Mastectomy144 (61.3)70 (66)
Radiotherapy  
 No193 (58.7)33 (26.8)
 Yes136 (41.3)90 (73.2)

Among the patients who received primary or neoadjuvant chemotherapy, 86% received surgery and 66% of the surgical procedures were mastectomies. At the time of surgery, 64% of these patients had Stage II–IIIA disease. Most of these patients also received adjuvant therapy and taxanes in either the neoadjuvant or adjuvant setting. Approximately one-half of the patients received tamoxifen in either the neoadjuvant or adjuvant setting, and 73% received radiotherapy. Patients who received neoadjuvant chemotherapy tended to have smaller tumors yet more positive lymph nodes at the time of surgery compared with patients who did not receive neoadjuvant chemotherapy.

Table 3 shows the estimates of RFS for this population overall and by certain patient and disease characteristics. There were 175 patients with disease recurrence. The estimate of RFS at 5 years was 48% (95% confidence interval [95% CI], 41–54%). Few patients reported a family history of ovarian carcinoma. However, these patients tended to have shorter RFS than patients who did not report a family history of ovarian carcinoma (P < 0.0001). Patients whose tumor specimens were ER/PR negative tended to have shorter RFS than patients whose tumors were ER/PR positive (P = 0.001).

Table 3. Disease Recurrence-Free Survival Estimates
CharacteristicsNo. of patientsNo. of Events5-yr estimate (%)95% CILog-rar P value
  1. 95% CI: 95% confidence interval; BMI: body mass index; ER: estrogen receptor; PR: progesterone receptor.

Overall4521754841–54% 
Obesity     
 BMI < 303311274942–57% 
 BMI ≥ 3084443825–51%0.01
Race     
 Asian184410–83% 
 Black43155636–76% 
 Other9500–0% 
 Hispanic85304731–63% 
 White2971214740–55%0.19
Oral contraception use     
 No219864535–54% 
 Yes233895042–59%0.98
Family history of breast carcinoma     
 No2981224536–53% 
 Yes154535343–64%0.16
Family history of ovarian carcinoma     
 No4291614943–56% 
 Yes2314130–34%<0.00
Nuclear grade     
 1115428–77% 
 2113434531–59% 
 32811164739–55%0.19
HER-2/neu     
 Negative181753624–49% 
 Positive92413723–52%0.82
ER and PR     
 Both negative150694029–51% 
 Either positive241925041–59%0.001

Table 4 shows the estimates of OS for this population. There were 84 deaths and the estimate of OS at 5 years was 77% (95% CI, 72–83%). Similar to RFS, patients who reported a family history of ovarian carcinoma or whose tumors were ER/PR negative tended to have a shorter OS. In addition, patients with Black's nuclear Grade 3 disease tended to have a shorter OS than patients with nuclear Grade 1 or 2 disease (P = 0.005).

Table 4. Overall Survival Estimates
CharacteristicsNo. of patientsNo. of events5-yr estimate (%)95% CILog-P-value
  1. 95% CI: 95% confidence interval; BMI: body mass index; ER: estrogen receptor; PR: progesterone receptor.

Overall452847772–83% 
Obesity     
 BMI < 30331657771–84% 
 BMI ≥ 3084177767–88%0.0
Race     
 Asian1837747–100% 
 Black4368673–99% 
 Other927545–100% 
 Hispanic85128170–92% 
 White297617669–82%0.0
Oral contraception use     
 No219447567–83% 
 Yes233407972–86%0.0
Family history of breast carcinoma     
 No298597972–85% 
 Yes154257465–84%0.0
Family history of ovarian carcinoma     
 No429767974–84% 
 Yes2384412–77%0.0
Nuclear grade     
 11135616–95% 
 2113138778–96% 
 3281627467–81%0.0
HER-2/neu     
 Negative181257868–87% 
 Positive92207461–86%0.0
ER and PR     
 Both negative150426050–71% 
 Either positive241338680–92%< 0.00

Tables 5 and 6 present the results from the Cox proportional hazards models of RFS and OS, respectively. Family history of ovarian carcinoma and nuclear grade remained significant at the P = 0.05 level. Patients who reported a family history of ovarian carcinoma had an increased risk of disease recurrence and death compared with patients who did not. Patients with Black's nuclear Grades 3 or 2 disease had a lower risk of disease recurrence compared with patients with Black's nuclear Grade 1 disease.

Table 5. Cox Proportional Hazards Model of Disease Recurrence-Free Survival
CharacteristicsHazard ratio95% CIP-value
  1. 95% CI: 95% confidence interval.

Obesity1.020.59–1.77%0.94
AsianReference  
Black1.240.24–6.34%0.79
Other1.740.22–13.82%0.60
Hispanic1.420.31–6.48%0.65
White1.650.39–7.02%0.50
Oral contraception use0.750.47–1.2%0.23
Family history of breast carcinoma0.700.42–1.18%0.18
Family history of ovarian carcinoma2.691.21–6%0.02
Nuclear grade   
 1Reference  
 20.210.05–0.85%0.03
 30.530.15–1.92%0.33
Table 6. Cox Proportional Hazards Model of Overall Survival
CharacteristicsHazard ratio95% CIP-value
  1. 95% CI: 95% confidence interval.

Obesity1.420.99–2.04%0.06
AsianReference  
Black1.350.38–4.84%0.65
Other4.281–18.28%0.05
Hispanic1.950.59–6.46%0.28
White2.070.64–6.66%0.22
Oral contraception use0.950.69–1.32%0.76
Family history of breast carcinoma0.740.52–1.05%0.09
Family history of ovarian carcinoma2.981.65–5.38%0.0003
Nuclear grade   
 1Reference  
 20.630.22–1.84%0.40
 30.850.31–2.39%0.76

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The current study describes a large cohort of patients with breast carcinoma age ≤ 35 years treated in a single institution, their characteristics at diagnosis, and the association of these characteristics with disease recurrence and survival.

Breast carcinoma arising at a young age may be considered different from that developed by older women.11 Initially, menopausal status was considered as a divider for different disease etiologies,12 not only because of variation in incidence rates,13 but also because of different risk factors.14 The risk for premenopausal breast carcinoma has been reported to be elevated in African-American patients, in women with lower BMI, and in patients with a recent history of oral contraception use.14–16

Tumor specimens from young patients have been reported to have poor biologic features that lead to a less favorable prognosis.3, 17 Our results, however, are limited by self-reports and by missing more aggressive biologic features such as HER-2/neu. Reports concerning age and prognosis have shown that high tumor grade represents a discriminatory prognostic factor between younger and older premenopausal patients with operable breast carcinoma.18 Conversely, the presence of positive ER in young patients seems to have a different prognostic value. Data suggest that very young women with endocrine-responsive tumors had a statistically significantly higher risk of disease recurrence than older premenopausal patients with such tumors. In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine nonresponsive.19, 20

The current analysis shows that after adjustment for obesity, race, self-report of any oral contraception use, self-report of a family history of breast and ovarian carcinoma, and poor nuclear grade remained associated with poorer RFS among these patients. Similarly, self-report of a family history of ovarian carcinoma remained associated with poorer OS among these patients.

Perhaps, the most noteworthy finding of our analysis is the association of self-report of a family history of ovarian carcinoma with shorter RFS and OS. However, this could be a spurious finding, given the small number of patients with a family history of ovarian carcinoma and that family history was self-reported. In a recently published, population-based study, the authors21 demonstrated that women with breast carcinoma with a first-degree family history of breast and ovarian carcinoma diagnosed and followed until death, emigration, or end of follow-up (n = 2175 [12.7%]) had a similar prognosis to women without any family history. The hazard ratio of death was 0.86 (95% CI, 0.71–1.05). This appeared unrelated to age at diagnosis either in the index patient or in the relative(s) with breast and/or ovarian carcinoma.21 Other studies report worse prognosis for familial breast carcinoma.22 However, there may be heterogeneity among familial breast carcinomas, such as the one described using gene expression pattern.23 In addition, the presence of BRCA1 and BRCA2 gene mutations can influence survival.24 Previous studies that have compared survival between patients with breast carcinoma with and without a family history have found inconsistent results. This can be due to different definition criteria of family history, which may attenuate or increase any true association between familial disease and prognosis. Conversely, investigators identify patients with breast carcinoma in centers for genetic counseling or from specific ethnic groups where inherited disease genes are more prevalent, as among Ashkenazi Jews.25, 26 Our data indicate that breast carcinoma in young patients with family members who had ovarian carcinoma may have a worse prognosis and need to be studied prospectively.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES