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Cancer in Pregnancy: Critical review of the effects of prior and subsequent pregnancy on the prognosis of young women with breast cancer
The time interval between a prior pregnancy and the diagnosis of breast cancer inversely correlates with 5 year survival rates. The shorter this time interval, the greatest risk for death. This correlation is expecially strong for a pregnancy within 2 years prior to the diagnosis of breast cancer. Five year survival rates ranged from 50 - 58% among women who had been pregnant within 48 months prior to the diagnosis of breast cancer compared to the 75 - 78% among age-matched breast cancer patients without a previous pregnancy. Women diagnosed with breast cancer during pregnancy demonstrated the poorer 5 year survival rates (40%). Survival rates reach comparable values between breast cancer patients without a prior pregnancy and those with a prior pregnancy only when the most recent pregnancy had been 5 years or more before the diagnosis of breast cancer. Comparable survival rates have been demonstrated for diagnosis of breast cancer patients with and without a subsequent pregnancy, with some reports even suggesting a "protective effect" of a pregnancy following treatment for breast cancer.
A pregnancy within 5 years prior to the diagnosis of breast cancer is a negative prognostic factor. The shorter the time lag between the most recent pregnancy and the diagnosis of breast cancer the greatest the risk for death. In contrast, a pregnancy subsequent to the diagnosis of breast cancer appears to impose no negative prognostic influence.
Breast cancer is the most common malignancy associated with pregnancy 1. As estrogen and progesterone are well established growth factors in breast cancer, 2 and since a woman's reproductive history is associated with the risk of developing breast cancer, 3,4 the hormonal changes associated with pregnancy, could at least theoretically have negative effects on the prognosis of breast cancer.
According to different reports 3-20% of the 186,000 annual cases of breast cancer will occur in women of childbearing age 5-7. It is therefore not surprising that many breast carcinoma patients have sought medical advice regarding the effects of becoming pregnant after successful breast carcinoma treatment. The literature on this topic is far from being consistent: some previous studies have found breast cancer concurrent with pregnancy to have a poor prognosis, whereas others have not. Different causes were used to explain the conflicting reports. As the majority of previous studies included small numbers of cases, they were unable to correct for significant confounders such as tumor size, axillary lymph node status, histological grading and the time interval between pregnancy and the diagnosis of breast cancer. Furthermore, some large case series included patients treated 40-50 years ago, when both obstetric and breast cancer management and therefore prognosis differed substantially from today. Finally, many studies have combined data from both post partum and prior pregnancies which can mask potential distinctive effects of each one of those conditions. The objective of our study was to perform a critical review of existing evidence regarding the effects of both prior and subsequent pregnancies on the prognosis of breast cancer.
We conducted a literature search of the MEDLINE database from 1966 to 1997. In the search we used the text words "breast cancer", "breast carcinoma", "breast malignancy", "malignant breast tumors", "mammary cancer", "mammary carcinoma" and "pregnancy". We obtained additional studies from reference lists of retrieved articles.
As breast cancer management and prognosis have changed substantially over the last 5 decades, we included mainly trials from 1970 and later. We have also focused on large sample-sized reports (including more than 50 patients) all of which have analyzed their data after adjusting for all the important confounders. Finally, we examined separately the effect of prior and subsequent pregnancies on the prognosis of breast cancer.Effects of prior pregnancy on the prognosis of women with breast cancer
In a multicentre study, 407 women aged 20-29 who were pregnant prior to the diagnosis of breast cancer, were followed at one of nine cancer centers between 1978 and 1988 8. After adjusting for tumor size, axillary node status and estrogen receptor status, the calculated 5 year survival of the patients who were pregnant at the time of breast cancer diagnosis was significantly lower than that of patients who had remote pregnancies (40% vs. 65%; p=0.0005). These differences became even more pronounced when these patients were compared to breast cancer patients who had not been pregnant before (5 year survival rates of 40% vs. 74%; p=0.0001). Even after adjustment for important confounders such as tumor size and nodal status and after stratification by institution and treatment, the differences remained statistically significant (p=0.023).
Survival curves of 291 women for whom data on the most recent pregnancy was available, have shown positive correlation between the time lag to the most recent pregnancy and the 5 and 10 year survival: only 40% of the women who were pregnant at the time of breast cancer diagnosis, had survived 5 years compared to 50% in the women who were diagnosed within 0-12 months from the last pregnancy, 60% in those who were diagnosed 13-48 months after their most recent pregnancy and 74% in those who had no previous pregnancies. However it is important to note that these data were not adjusted for tumor size and nodal status.
Another population-based analysis 9, has revealed that the time since the last childbirth is an important prognostic factor in primary breast cancer: women who were diagnosed with breast cancer in the first two years following the last childbirth, had a significantly poorer survival compared to women who gave birth 5 or more years previously (RR=1.58, 95% CI 1.24 to 2.02). These findings persisted after adjusting for tumor characteristics (tumor size, number of positive axillary nodes, grade of anaplasia) and adjuvant chemotherapy. The time interval between the most recent birth demonstrated a significant correlation with survival rates of breast cancer: pregnancy within one year of breast cancer diagnosis was associated with 2.1 fold increase for death while a 1.3-fold increase has been demonstrated for pregnancies within the second year.
The significance of the time between the last pregnancy and the diagnosis of breast cancer as a prognostic factor was further emphasized by different independent reports including together 411 breast cancer patients diagnosed during gestation or lactation, all of which have demonstrated significantly lower 5 year survival rates among the study patients compared to age and stage-matched controls without a prior pregnancy 10-15.
Worthy to note, there was a tendency for a more advanced disease in women who were pregnant at the time of breast cancer diagnosis compared to those who had remote pregnancies in relation to their breast cancer diagnosis 11,14,16. This may reflect the difficulties and therefore delayed diagnosis of breast cancer in pregnant women especially because of pregnancy-related hormonal-induced changes in the mammary tissue. However, after correcting for this confounder, recent pregnancy has been still shown to be a factor affecting the prognosis of breast cancer suggesting an independent biological effect of a recent pregnancy on breast cancer prognosis rather than just a factor delaying the diagnosis.
In a recent study conducted by us, we showed that women with breast cancer in pregnancy had a substantially higher risk of metastatic disease as compared from the population distribution, and these results corroborate the above mentioned analyses 17 . In trying to further assess whether stage-for-stage, breast cancer in pregnancy is more virulent, we compared survival rates of 118 women with breast cancer and pregnancies to 269 breast cancer controls matched for stage of disease, age and therapeutic protocol 17. Five, 10 and 25 year survival rates did not differ between the pregnant and non-pregnant groups (p=0.6).
In contrast to the above mentioned reports, patients who were diagnosed with breast cancer prior to or during pregnancy have demonstrated identical survival rates compared to the control group over 15 year period of follow up. These findings were further supported by three independent reports including 304 breast cancer patients associated with pregnancy who have also shown comparable 5 and 10 year survival rates to controls 18-20. However, it is important to recognize significant limitations of these reports some of which did not include a control group 19, while the others 18,20 suffered from a limited sample size making them unable to sub-analyze the influence of important confounders such as the time since the most recent childbirth as an independent prognostic factor.
It is possible that analyses which have not taken into account the time interval between the most recent pregnancy and the diagnosis of breast cancer as a potential risk factor may have masked the significance of its prognostic factor. This can also explain the comparable survival rates in these studies which have dealt with all the women with a pregnancy prior to the diagnosis of breast cancer regardless of the time that has passed since the most recent pregnancy and the diagnosis of breast cancer. Moreover, it appears that in all the studies which have included the time lag between the most recent pregnancy in their analysis it came up as an important negative prognostic factor.
Effects of subsequent pregnancy on prognosis of women with breast cancer
The question of whether a subsequent pregnancy influences the survival of patients treated for breast carcinoma is based on the hypothesis that the hormonal changes associated with gestation might stimulate growth of the residual breast cancer cells.
In the most recent report 5725 women with primary breast cancer were followed for a total of 35,067 patient years.22 One hundred and seventy three (3%) women had 211 pregnancies. Tumor characteristics, age at diagnosis, year of treatment and therapeutic protocol assignment were all introduced into a multivariate analysis, and association with survival was analyzed using the Cox's proportional hazards method. Women who completed a full term pregnancy showed a reduced risk for death compared to breast cancer women with no pregnancy (RR=0.55 95% CI 0.28 to 1.06).
Age at diagnosis, tumor size, regional lymph node status, time since the last pregnancy did not alter the influence of pregnancy on breast cancer prognosis. Importantly, recurrence rate was not affected by pregnancy as well.
In a population-based study including 2548 women diagnosed with carcinoma of the breast, 91 were identified with subsequent deliveries 23. Four hundred and seventy one controls were matched for stage of disease, age and year of breast cancer diagnosis. The controls demonstrated a 4.8 fold risk (95% CI 2.2 to 10.3) for death compared to the study group. Furthermore, there was a significant correlation between the interval from breast cancer diagnosis to the subsequent delivery: the controls have demonstrated the highest relative risk (11.3 95% CI 1.6 to 82.8) when compared to breast cancer patients with a subsequent pregnancy within 10-24 months after the diagnosis of breast cancer. A relative risk of 2.6 (95% CI 1.1 to 6.0) has been observed when the control group was compared to breast cancer patients with a subsequent pregnancy 25-60 months post partum.
Potential "protective effect"
Interestingly, a potential "protective effect" of a subsequent pregnancy on the prognosis of breast cancer was observed also by Peters et al. who presented data demonstrating improved survival rates among patients seen at the Ontario Cancer Institute 23. The author even suggested that breast cancer patients should be encouraged to plan pregnancies in an attempt to improve their chances of survival.
Although other studies have failed to demonstrate a protective effect of a subsequent pregnancy , all of them have demonstrated comparable survival rates between the study groups (i.e. breast cancer women with post partum pregnancy) and matched controls 12,24-28. Five year survival rates ranged between 71%-80% according to different reports, and ten year survival of a negative lymph node cohort was reported to be 90% with no differences between the cases and matched controls. To further support these findings, it has been demonstrated in several studies that therapeutic abortion in pregnancies subsequent to the treatment of breast cancer did not improve survival rates.
Despite the consistency of these reports, all these studies but one suffer from a relatively limited sample size and lack therefore the important sub-analysis looking at the potential prognostic effect of the time interval between the diagnosis of breast cancer and a subsequent pregnancy. Only in the largest study including 136 patients the effect of the interval between breast carcinoma treatment and subsequent pregnancy has been studied 12. This report has demonstrated that women who became pregnant within 6 months following treatment for breast cancer had poorer five year survival rates compared to those who deferred pregnancy from 6 to 24 months (53.8% vs. 78%). Moreover, women who became pregnant five years or more after breast cancer treatment have demonstrated 5 year survival rates which were not different from those of breast cancer patients which did not become pregnant.
Contrary to the theoretical expectations, older reports tended to identify no negative effects of pregnancy on the prognosis of breast cancer. However, most of these studies were limited with respect to their sample size and therefore their ability to correct for confounders. To overcome these limitations, multi center and population-based studies have been recently conducted. From these reports, it appears that the prognosis of breast cancer is worse for patients who were pregnant at the time of diagnosis than those who had previously been pregnant or those who had never been pregnant. Moreover, the shorter the time lag between a pregnancy and the diagnosis of breast cancer the greatest the risk for death. This condition by its nature limits our ability to intervene but it definitely should be included when counseling a patient with breast cancer and a recent pregnancy.
In contrast to this condition, a pregnancy subsequent to the diagnosis of breast cancer appears to impose no negative prognostic influence on breast cancer. These data from older reports were recently supported by a population-based data including a large sample size. Although some studies have even suggested a "protective effect" of a subsequent pregnancy on the prognosis of breast cancer this effect may only represent a selection bias of a "healthier cohort" (i.e. those who became pregnant after treatment for breast cancer) . When advising breast cancer patients about the potential effects of a subsequent pregnancy, it seems that there is no evidence that pregnancy adversely influences the clinical course of the disease although larger prospective studies are needed to confirm these findings.
Table 1 --
The major studies reporting on the effect of prior pregnancy on the prognosis of young women with breast cancer.
|Schoults et al. J. Clin. Oncol 1995||173||1740||Development of distant metastases did not differ between the study and control group. RR=1.02||No effect of the time between conception and diagnosis and the development of distant metastases.|
|Guinee et al. Lancet 1994||407||139||5 year survival rates: 40% for women who were pregnant at the time of breast cancer diagnosis vs. 65% for women who had previous pregnancies and 75% for those who had never been pregnant.||For each 1 year increment in the time between the latest previous pregnancy and breast cancer diagnosis the risk of dying decreased by 15%. Highest risk for death when breast cancer was diagnosed during pregnancy.|
|Kromas et al. Br. Med J 1997||4975||No||5 year survival rates: 58.7% for women with breast cancer diagnosed within 2 years after the last childbirth vs. 78.4% for those diagnosed more than 2 years. RR=1.58.||The risk of dying from breast cancer associated with a recent birth was increased 2.1-fold for a pregnancy within 1 year prior to the diagnosis of breast cancer and 1.3-fold for a pregnancy within 2 years prior to the diagnosis.|
|Petrek et al. Cancer 1991||56||166||No differences in 5 and 10 year survival rates in the study and the control group. RR=0.67||No analysis of the time between conception and the diagnosis of breast cancer and survival rates.|
|Tretly et. al. Br J Cancer 1988||20 patients diagnosed during pregnancy; 15 during lactation||140||5 year survival rates in pregnancy-associated breast cancer- significantly lower compared to controls. RR for death = 3.1||No analysis of the time interval between pregnancy and the diagnosis of breast cancer and survival rates.|
|Zemlickis et al. Am J Obst Gyn 1992||118||269||No differences in 5, 10 and 25 year survival rates between the study and the control groups.||No analysis of the time interval between pregnancy and the diagnosis of breast cancer and survival rates. Poorer prognosis for women diagnosed with breast cancer during pregnancy.|
- Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Maternal and fetal outcome following breast cancer in pregnancy. In Cancer in pregnancy, Koren G, Lishner M Farine D. (editors) pp 95-106. Cambridge University Press.
- Bergqvist L, Adami HO, Persson I et al. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989; 321:293-297.
- Ewertz M, Duffy SW, Adami HO et al. Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the nordic countries. Int J Cancer 1990; 46:597-603.
- Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993; 15:36-47.
- Anderson JM. Mammary cancers and pregnancy. Br Med J 1979; 1:1124-1127.
- Parente JT, Amsel M, Lerner R, Chinea F. Breast cancer associated with pregnancy. Obstet Gynacol 1988; 71(6): 861-864.
- Surbone A, Petrek JA. Childbearing issues in breast carcinoma survivors. Cancer 1997; 79(7): 1271-1278.
- Guinee VF, Olsson H, Moller T et al. Effect of pregnancy on prognosis for young women with breast cancer. Lancet 1994; 343: 1587-1589.
- Kroman N, Wohlfahrt J, West K et al. Time since childbirth and prognosis in primary breast cancer: population-based study. Br Med J 1997; 315: 851-855.
- Tretli S, Kvalheim G, Thoresen S, Host H. Survival of breast cancer patients diagnosed during pregnancy or lactation. Br J Cancer 1988; 58: 382-384.
- Anderson BO, Petrek JA, Byrd DR, Senie RT, Borgen PI. Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger. Annals of Surg Oncol 1996; 3(2): 204-211.
- Clark RM, Chua T. Breast cancer and pregnancy: the ultimate challenge. Clin Oncol R Coll Radiol 1989; 1:11-18.
- Makita M, Sakamoto G, Namba K, Akiyama F, Iwase T, Sugano H, Sato Y, Kasumi F, Nishi M. Study of breast cancer during pregnancy and lactation. Japanese J of Cancer Clinic 1990; 36(1): 39-44.
- Bonnier P, Romain S, Dilhuydy JM, Bonichon F, Julien JP, Charpin C, Lejeune C, Martin PM, Piana L. Influence of pregnancy on the outcome of breast cancer: a case-control study. International J of Cancer 1997; 72(5): 720-727.
- Ishida T, Yokoe T, Kasumi F, Sakamoto G, Makita M, Tominaga T, Simozuma K, Enomoto K, Fujiwara K, Nanasawa T. Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: analysis of case-control study in Japan. Japanese Journal of Cancer Research 1992; 83(11) 1143-1149.
- Petrek JA, Dukoff R, Rogatko A. Prognosis of pregnancy-associated breast cancer. Cancer 1991; 67: 869-872.
- Zemlickis D, Lishner M, Degendorfer P, et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992; 166: 781-787.
- Schoultz E, Johansson H, Wilking N, Rutqvist LE. Influence of prior and subsequent pregnancy on breast cancer prognosis. J Clin Oncol 1995; 13: 430-434.
- Ribeiro G, Jones DA, Jones M. Carcinoma of the breast associated with pregnancy. Br J Surgery 1986; 73: 607-609.
- King RM, Welch JS, Martin JK, Coulam CB. Carcinoma of the breast associated with pregnancy. Surgery, Gynecology and Obstetrics 1985; 160: 228-232.
- Kroman N, jensen MB, Melbye M et al. Should women be advised against pregnancy after breast cancer treatment? Lancet 1997; 350: 319-322.
- Sankila R, Heinavaara S, Hakulinen T. Survival of breast cancer patients after subsequent term pregnancy: "Healthy mother effect". Am J Obstet Gynecol 1994; 170:818-823.
- Peters MV. The effect of pregnancy in breast cancer. In: Prognostic factors in breast cancer. Edited by APM Forrest and PB Kunkler pp 65-80. London E&M Livingston 1968.
- Cooper DR, Butterfield J. Pregnancy subsequent to mastectomy for cancer of the breast. Ann Surg 1970; 171: 429-433.
- Harvey JC, Rosen PP, Ashikari R et al. The effect of pregnancy on the prognosis of carcinoma of the breast following radical mastectomy. Surg Gynecol Obstet 1981; 153: 723-725.
- Mignot L, Morvan F, Berdah J. Pregnancy after breast cancer: results of a case control study Presse Med 1986; 15: 1961-1964.
- Ariel I, Kempner R. The prognosis of patients who become pregnant after mastectomy for breast cancer . Int Surg 1989; 74: 185-187.
- Mignot L, Morvan F, Berdah J, Querleu D, Laurent JC, Verhaeghe M, Fontaine F, Marin JL, Gorins A, Marty M. Pregnancy after treated breast cancer. Results of a case-control study. Pressee Medicale 1986; 15(39): 1961-1964.