Effects of pregnancy after treatment for breast carcinoma on survival and risk of recurrence

Authors


Abstract

BACKGROUND

The goal of the current study was to assess the effect of pregnancy on the subsequent risk of recurrence after treatment for breast carcinoma, adjusting for established prognostic factors.

METHODS

Between 1974 and 1998, 383 patients age ≤ 35 years were treated for breast carcinoma with adjuvant chemotherapy at The University of Texas M. D. Anderson Cancer Center (Houston, TX). The median follow-up period was 13 years. Of these, 13 patients were excluded from analysis, as no history was available regarding pregnancy; 240 (65%) were > 30 years old; 47 (13%) had at least 1 pregnancy after therapy; 32 had full- term pregnancies; 10 had spontaneous or elective abortions; 4 had miscarriages; and 1 had a premature delivery. Estrogen receptor (ER) status, lymph node involvement, and disease stage were evaluated as potential risk factors for recurrence. Information on ER status was unavailable for 123 (33%) patients.

RESULTS

Patients who experienced a pregnancy tended to have earlier-stage disease (Stage I/II: 80% vs. 73%), fewer positive lymph nodes (< 4: 87% vs. 52%), more ER negativity (68% vs. 58%), and younger age (< 30 years: 57% vs. 32%) than patients who did not. The incidence of disease recurrence was 23% for women who experienced a pregnancy and 54% for women who did not. The hazard ratio (using the multivariate Cox proportional hazards model) for disease recurrence in patients with posttreatment pregnancy was 0.71 (P = 0.4).

CONCLUSIONS

In the current study population, pregnancy was not associated with an increased risk of disease recurrence or poorer survival in patients previously treated for breast carcinoma. Cancer 2004. © 2003 American Cancer Society.

In the United States, there were 205,000 newly diagnosed cases of breast carcinoma and 40,000 deaths due to breast carcinoma in 2002.1 Approximately one-fourth of patients with breast carcinoma are diagnosed before the onset of menopause. Most of these women are treated with adjuvant or neoadjuvant chemotherapy, and in many of these patients, a predominant side effect is amenorrhea.2, 3 This is especially true for women who receive alkylating agents as part of their treatment regimens. Approximately 50% of women retain or resume ovarian function and continue to have regular menstrual cycles.4 There has been some concern regarding the effects of pregnancy on women with previous breast carcinoma because of a perceived increased risk in breast carcinoma occurrence in the first 1–2 years after primary cancer. The hazard rates for recurrent breast carcinoma after treatment for primary breast carcinoma continue to remain high for ≤ 10 years after treatment.5, 6

Breast carcinoma is, for the most part, hormone dependent, and pregnancy certainly is a condition in which hormone levels are at an all-time high. In the past, it was recommended that women not become pregnant after treatment for breast carcinoma.7 However, it has been shown that there is no increase in risk of death due to breast carcinoma in women who are pregnant at the time of diagnosis or who become pregnant after treatment of breast carcinoma.8–18 Most of these studies had small sample sizes and usually were retrospective case–control or observational studies, making data interpretation difficult for oncologists who rely on research data to provide the most informed counsel to their patients. The issue of pregnancy after the diagnosis of breast carcinoma remains controversial. Many authors recommend that women wait several years after the diagnosis and treatment of breast carcinoma before becoming pregnant.12, 16, 19–21 This issue is becoming more important, because women are delaying childbirth to a greater degree in our society. We report our experience over a 22-year period.

MATERIALS AND METHODS

Between 1974 and 1998, 383 patients < 35 years of age were treated for breast carcinoma with doxorubicin-containing adjuvant chemotherapies. All patients in the current study were treated in prospective adjuvant therapy trials. Each trial was reviewed and approved by the institutional review board. Each patient was informed about this research in accordance with institutional policy and written informed consent was obtained. The objectives of the current study were to assess the effects of pregnancy on cancer recurrence, with respect to established prognostic factors for breast carcinoma, subsequent to treatment for breast carcinoma.

Three hundred eighty-three patients were examined. Thirteen patients were excluded from the analysis due to missing information relating to pregnancy. The median follow-up for the total group was 123 months and the estimated 10-year survival rate was 55% (95% confidence interval [CI], 50–61%). One hundred eighty-four patients experienced disease recurrence. The estimated median time to disease recurrence was 98 months (95% CI, 54–156 months). Forty-seven patients had at least one pregnancy after adjuvant chemotherapy and provided complete information to allow for analysis.

Recurrence-free survival (RFS) was measured from the start of adjuvant chemotherapy to the date on which the first disease recurrence was detected or the date of last follow-up. Estimates of RFS were obtained by the Kaplan–Meier method, and comparisons were based on the two-tailed log-rank test. A Cox proportional hazards model22 was used to simultaneously consider the association between multiple patient covariates and the risk of disease recurrence. In addition to the inclusion of factors measured before treatment, the model included a time-dependent binary covariate that indicated whether a patient had become pregnant. Therefore, we investigated a potential change in risk of disease recurrence associated with the pregnancy event while adjusting for the impact of baseline prognostic factors.

RESULTS

Patient characteristics are summarized in Table 1. Forty-seven patients (13%) had at least 1 pregnancy after treatment for breast carcinoma. Of these patients, 32 had full-term pregnancies and the remaining 15 had either spontaneous or elected abortions (n = 10), miscarriages (n = 4), or preterm delivery (n = 1) (Table 2). After receiving chemotherapy, 203 (53%) patients resumed normal menstrual cycles and 44 (11%) became amenorrheic. Data were not available on the status of menstrual cycles after chemotherapy for 137 (36%) patients (Table 3). Of the 383 patients, 320 had at least 1 pregnancy. Patients who were rendered amenorrheic after chemotherapy had 36 pregnancies with 35 patients having at least 1 live birth. Of the patients who continued to have menstrual cycles after chemotherapy, 168 had at least 1 pregnancy, with 163 having at least 1 live birth. All of the patients were < 35 years old at treatment for breast carcinoma, and 65% were > 30 years old. A slightly larger percentage of the women who had posttreatment pregnancies were ≤ 30 years old compared with their nulliparous counterparts.

Table 1. Patient Characteristics
CharacteristicTotal (%)Pregnancy after treatment (%)No subsequent pregnancy (%)
  • ER: estrogen receptor.

  • a

    Supraclavicular lymph node involvement.

Age (yrs)   
≤ 30130 (35)27 (57)103 (32)
> 30240 (65)20 (43)220 (68)
Stage   
 I, IIA/B258 (74)33 (80)225 (73)
 III A/B, IVa 92 (26) 8 (20) 84 (27)
 Missing 20  
ER status   
 Positive101 (41)10 (32) 91 (42)
 Negative146 (59)21 (68)125 (58)
 Missing123  
Positive lymph nodes   
 0100 (28)19 (46) 81 (26)
 1–3129 (36)17 (41)112 (26)
 > 4129 (35) 5 (12)121 (39)
 Missing 15  
Table 2. Pregnancy Outcomes
OutcomeTotal (%)Alive (%)Dead (%)
Pregnancy 47 (13) 37 (79) 10 (21)
 Full term 32 (68)  
 Spontaneous or elective abortion 10 (21)  
 Miscarriage  4 (9)  
 Preterm  1 (2)  
No pregnancy323 (87)176 (54)147 (46)
Table 3. Menstruation and Pregnancy Data (Includes Data Obtained before and after Treatment)
CharacteristicMenstruation status after chemotherapy
UnknownMenstruatingAmenorrheic
All patients13720244
Pregnancy data   
 Unknown 123
 At least one pregnancy 16836
  At least one live birth 16335
 No pregnancy 225

Estrogen receptor (ER) status, lymph node status, and stage of disease at treatment for breast carcinoma were evaluated as potential prognostic factors for disease recurrence. Information on ER status was not available for 123 (33%) patients. Overall, ER status was more likely to be negative among patients for whom it was recorded. This result could be due to the age of the patients, as an ER-positive status is more often found in postmenopausal women or in women who are approximately age 50.

In the total group, the majority of patients (74%) had early-stage (Stage I/II) breast carcinoma at the time of treatment. The effect of disease stage on recurrence was evident in the RFS rates (Table 4). Patients who had Stage III/IV (Stage IV by supraclavicular lymph node) breast carcinoma had a poorer prognosis at 2 and 5-year RFS compared with patients with early-stage disease. Overall, cases were relatively evenly distributed across the three categories of lymph node status (0, 1–3, ≥ 4). When evaluated by lymph node category, patients with < 4 positive lymph nodes had better RFS than patients with ≥ 4 lymph nodes (Table 4).

Table 4. Outcomes and Estimated Recurrence-Free Survival Data
Characteristic2 yr RFSa (%)5 yr RFSa (%)Log-rank P value
  • RFS: recurrence-free survival; ER: estrogen receptor.

  • a

    Mean ± standard error.

  • b

    Supraclavicular lymph node involvement.

Pregnancy   
 Yes94 ± 482 ± 6 
 No69 ± 349 ± 3 
Stage   
 I, IIA/B78 ± 358 ± 3 
 IIIA/B, IVb59 ± 544 ± 50.007
Age (yrs)   
 ≤ 3070 ± 451 ± 5 
 > 3073 ± 354 ± 30.76
ER status   
 Positive78 ± 456 ± 5 
 Negative71 ± 455 ± 40.70
Positive lymph nodes   
 080 ± 463 ± 5 
 1–380 ± 463 ± 4 
 > 461 ± 439 ± 40.001

To understand the associations between potential prognostic factors and posttreatment pregnancy status, characteristics were summarized and analyzed according to the two pregnancy groups (Table 1). In general, the women who became pregnant were initially at some advantage regarding factors associated with the risk of disease recurrence. This group was more likely to have early-stage disease, fewer positive lymph nodes, and negative ER status. They also were younger than the women who did not become pregnant.

Statistical Analysis

The fitted Cox model resulted in an estimate of the regression coefficient for the time-dependent pregnancy term of −0.359, or a hazard ratio of 0.70 (95% CI, 0.25–1.95; P = 0.49). In this application, a hazard ratio < 1.0 indicates a reduced risk of disease recurrence. Baseline covariates included in the model were age (≤ 30 years or > 30 years), disease stage (I, II or III, IV), ER status (negative or positive), and involved lymph node status (0, 1–3, or ≥ 4). The 123 patients with unknown ER status were omitted from the modeling process. Similar findings for the pregnancy covariate were obtained in a second model that included all patients and excluded ER status as a covariate.

DISCUSSION

These data suggest that subsequent pregnancy after adequate therapy for breast carcinoma is not associated with an increased risk of death or disease recurrence. Women who had a pregnancy after treatment for breast carcinoma had earlier-stage disease and fewer positive lymph nodes compared with nulliparous women. These findings suggest that the women who experienced a pregnancy were destined to have a healthier outcome regardless of the pregnancy. After adjusting for the difference in prognostic factors using a statistical model, there was no real evidence that the pregnancy event significantly changed the subsequent risk of disease recurrence. Others have reported similar risk regardless of tumor size or the presence of lymph nodes.23 As expected, women with more advanced disease and more positive lymph nodes had a worse prognosis than women without these prognostic factors.

Studies in the United States and in other countries reported similar results (Table 5). Gelber et al.8 reported a decreased risk of death for women with subsequent pregnancy compared with matched controls (risk ratio, 0.44; 95% CI, 0.21–0.96; P = 0.04). A study performed in the state of Washington reported a relative risk (RR) of death associated with subsequent pregnancy of 0.8 (95% CI, 0.3–2.3).15 Similar studies from Denmark found that the RR of death in patients with subsequent pregnancy compared with controls was 0.55 (95% CI, 0.28–1.06).14, 23 A Swedish study found that the RR of death was 0.48 (95% CI, 0.18–1.29).13 In another study from Scandinavia, a group in Finland found that the control population had an increased risk of death due to breast carcinoma compared with women who had a subsequent pregnancy after treatment for breast carcinoma (RR, 4.8; 95% CI, 2.2–10.5).24 Overall, the evidence from the literature and from our study indicates that there is no increased risk of death from pregnancy after diagnosis and treatment of breast carcinoma. There may even be a slight protective effect.

Table 5. Comparison of Other Trials
StudyNo. of patientsOutcome of study
Gelber et al., 20018137Decreased risk in pregnant women
Velentgas et al., 19991553No adverse effect on survival
Kroman et al., 199714173Decreased risk in pregnant women
von Schoultz et al., 19951350No adverse effect on survival
Sankila et al., 19942491No adverse effect on survival ('healthy mother effect'?)
Sutton et al., 1990923No adverse effect on survival
Malamos et al., 19961121No adverse effect on survival
Ariel and Kempner, 19891847No adverse effect on survival

In the current study, there were 10 spontaneous or elective abortions and 4 miscarriages (29%), which is as high a rate of spontaneous abortion/miscarriage as was found in other studies. Some have reported a spontaneous abortion rate as high as 24%,15 whereas others have reported a rate as low as 10%.14 The high rate of abortion/miscarriage in the current study may be explained by the age of the women and changes to ovarian function that can occur after chemotherapy and/or radiotherapy. In one study, ≥ 50% of patients continued to menstruate after treatment with chemotherapy for breast carcinoma.4

The main limitation of the current and past studies is sample size. Although there were 383 patients < 35 years old treated with similar adjuvant chemotherapy regimens, only 47 had subsequent pregnancies. From the data available in the literature, subsequent pregnancy does not adversely affect overall survival and may, in fact, have a beneficial effect. The biologic effect, if any, on improvement of survival is clearly not understood. The women who do become pregnant may be healthier than women who do not, so there may be some inherent selection bias. In our study, women who later became pregnant had earlier-stage disease, fewer positive lymph nodes, had ER-negative tumors more often, and were younger than women who did not have subsequent pregnancies. Unfortunately, ER status was not available for 33% of the women in the current study. The finding that the women who had pregnancies after treatment for breast carcinoma in our study were also more likely to have ER-negative tumors may be a result of their younger age as well.

Given our results and the results of others, there is no reason to discourage women who have been treated for breast carcinoma from bearing children. Today, more women in the United States are choosing to delay childbearing for a variety of personal reasons. Therefore, more clinicians may face counseling these women on the decision to go forward with pregnancy after the diagnosis and treatment of breast carcinoma. For women with early-stage disease, pregnancy itself does not seem to increase their risk of death after treatment for breast carcinoma. However, there does seem to be a higher rate of spontaneous abortion/miscarriage among women treated for breast carcinoma. The etiology of this phenomenon is largely unknown. Ultimately, the decision of conception remains with the patient, but physicians should be aware of the issues so as to properly counsel their patients.

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