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2301
E D I T O R I A L
Pregnancy after Breast
Carcinoma
The Ultimate Medical Challenge
Hervy E. Averette, M.D.1
Ramin Mirhashemi, M.D.1
Frederick L. Moffat, M.D.2
1
Division of Gynecologic Oncology, University of Miami, School of Medicine, Sylvester
Comprehensive Cancer Center, Miami, Florida.
2
Division of Surgical Oncology, University of Miami, School of Medicine, Sylvester Comprehensive
Cancer Center, Miami, Florida.
he report by Velentgas et al.1 in this issue of Cancer addresses an
important issue in the management of premenopausal breast
carcinoma survivors. This subgroup of patients frequently has questions and concerns regarding future childbearing, in particular the
plausibility of fertility after systemic chemotherapy and the risk of
recurrence and overall survival due to pregnancy. The authors in this
study concluded that pregnancy after breast carcinoma does not
appear to have an adverse effect on survival. In addition, they state
that the rate of miscarriages among women who become pregnant
after breast carcinoma is higher than expected.
It is difficult to ignore the strong body of evidence linking reproductive history to breast carcinoma. The risk of developing breast
carcinoma decreases by 25% for each year that menarche is delayed
and the relative risk is 0.73 for those women whose natural menopause occurs before age 45 years compared with those women whose
natural menopause occurs between the ages of 45–54 years.2 In contrast, multiparity, young age at first pregnancy, and history of breastfeeding all appear to create a protective effect on breast carcinoma
risk. In addition, surgical castration (oophorectomy) has been reported to reduce the risk of breast carcinoma in animals and humans.3 Women who undergo oophorectomy before the age of 35
years have a 50% reduction in the risk of breast carcinoma. The
common link between these protective factors appears to be the
cumulative lifetime exposure to estrogen. This correlation has contributed strongly to the belief that hormonal milieu is a factor for the
development and possible progression of breast carcinoma. One of
the most profound hormonal changes in a woman’s lifetime is pregnancy. There have been many studies evaluating the prognosis of
patients diagnosed with breast carcinoma during pregnancy and
when matched for age and stage of disease, patients with breast
carcinoma during pregnancy have the same prognosis as nonpregnant patients.
The immunologic effects of pregnancy on breast carcinoma also
are a topic of discussion. According to data first collected in Utah and
T
See referenced original article on pages 2424 –32.
Address for reprints: Hervy E. Averette, M.D., Division of Gynecologic Oncology, University of Miami, School of Medicine, Sylvester Comprehensive
Cancer Center, 1475 N.W. 12th Avenue, D-52,
Miami, FL 33136.
Received March 5, 1999; accepted March 8, 1999.
© 1999 American Cancer Society
2302
CANCER June 1, 1999 / Volume 85 / Number 11
later confirmed in New York, there may be an immunization against breast carcinoma that occurs during
pregnancy.4 The “fetal antigen hypothesis” suggests
the possibility that breast carcinoma cells and fetal
cells share common antigens. During pregnancy, a
woman develops a form of isoimmunization that in
turn protects her against breast carcinoma.5 This theory may be applicable to patients with a history of
breast carcinoma. According to this hypothesis, fetal
antigens during pregnancy can elicit a strong memory
response from the immune system (primed from previous exposure to breast carcinoma cells), with the
generation of a specific cellular and humoral response. As a result, subclinical micrometastases are
kept in check by the immune system.
The current study by Velentgas et al. is particularly
timely because it comes at a time when American
women are opting for later childbirth and the incidence of breast carcinoma continues to rise in all age
groups. Approximately 25% of women will develop
breast carcinoma in their premenopausal years and
still may wish to bear children. The concern with
subsequent pregnancy after breast carcinoma treatment is that of dormant micrometastases stimulated
by gestational systemic hormones. This concern was
addressed in a 1994 study from cancer centers in five
countries.6 They noted that survival proportionately
was better with a longer interval between pregnancy
and breast carcinoma diagnosis (up to 4 years). Because the detrimental effect of pregnancy was reported up to 4 years after treatment for breast carcinoma, this study supports the promotional influence
of gestational hormones on existent, but subclinical,
disease. Although the promotional effect of pregnancy
is suggested in this particular study, to our knowledge
there are seven published reports implying that subsequent pregnancy after breast carcinoma is safe
when corrected for stage of the tumor.7-13
There certainly are some limitations to the current
study by Velentgas et al. as well as other published
reports. To our knowledge, with the exception of two
Scandinavian studies, all the reports regarding this
topic are retrospective series with cases retrieved
based on memory of the treating physician, review of
hospital records, and/or interview with family members. The number of reported pregnancies after breast
carcinoma is fairly small when compared with the
estimated number of young breast carcinoma survivors who may become pregnant. Furthermore, the
potential for selection bias in these retrospective studies is enormous. A form of bias termed “healthy
mother effect” may occur because patients who give
birth have to survive at least until the delivery and may
be more likely to be free of disease at the time of
pregnancy. Data regarding how many pregnancies
have occurred in breast carcinoma survivors are vague
because many result in unrecognized spontaneous
abortion or unreported induced abortion. The potential for these biases has been acknowledged appropriately in the study by Velentgas et al.
The interval between breast carcinoma diagnosis
and pregnancy also is an important factor and needs
to be addressed further. It is difficult to analyze the
effect that the interval between treatment and pregnancy has on overall prognosis because women who
defer pregnancy for many years also are those who
have remained disease free for longer periods and in
general have less aggressive malignancies and better
prognoses. Clark and Reid found that those patients
who became pregnant within 6 months of treatment
had a 5-year survival rate of 54% compared with a
5-year survival rate of 78% for patients who waited 6
months to 2 years.14 In contrast, Mignot et al. found
no statistical difference in outcome between patients
who conceived within 6 months of treatment versus
those who had conceived later.15 Recurrence rates for
breast carcinoma are highest during the first 2 years
after treatment; therefore, it may be prudent to defer
pregnancy until 2 years after the completion of therapy. Thus, the importance of timing correlates more
with the breast carcinoma prognosis than with any
other effect that pregnancy may have on prognosis.
Another question of interest is whether interrupting the pregnancy will affect prognosis. Clark and Reid
noted that those patients who had a therapeutic or
spontaneous abortion had lower survival rates when
compared with those patients who continued their
pregnancy to term.14 However, to our knowledge the
majority of reports regarding this topic conclude that
abortion appears to have no favorable influence on
outcome and should not be recommended, at least for
patients with limited (lymph node negative) disease.16
Many patients with Stage I or Stage II breast carcinoma are treated with adjuvant chemotherapy. The
complex issue of chemotherapy-induced ovarian failure is another important predicament facing young
breast carcinoma survivors. A discussion of this topic
is beyond the scope of this editorial, but suffice it to
say that the use of alkylating or alkylating-like agents
are correlated strongly with premature menopause
and poor ovarian function. Velentgas et al. observed a
higher rate of spontaneous abortions in their study
group compared with a control group of patients without breast carcinoma (24% vs. 18%). Their findings are
consistent with the literature in other human malignancies. Mulvihill et al. reported on 40 women who
had a total of 59 pregnancies after treatment for
Hodgkin lymphoma, the majority of whom had un-
2303
dergone chemotherapy as part of their treatment.17
They noted a significantly higher spontaneous abortion rate compared with the general population. They
concluded that this could be due to defects in hormonal factors that normally maintain gestation, presumably secondary to chemotherapy-induced ovarian
dysfunction. In their discussion Velentgas et al. point
out that the proportion of women who had undergone
adjuvant chemotherapy or radiation therapy did not
appear to differ among the women who had miscarriages and the women with other pregnancy outcomes.1 However, this does not explain the higher
miscarriage rate in their population compared with
the general population. Furthermore, they state that .
50% of the women who miscarried after breast carcinoma also delivered at least 1 live-born infant.1 This
statement is misleading due to the lack of data clarifying whether the aforementioned group of patients
received adjuvant chemotherapy and/or radiation
therapy. To understand better the etiology of the
higher rate of spontaneous abortions in breast carcinoma survivors, one would need to perform serum
studies of hormone levels during the first and second
trimesters of pregnancy.
Some women, aware of the risk of chemotherapyinduced ovarian failure, have elected to maintain fertility potential via assisted reproductive techniques.
The advancements in the field of cryopreservation of
patients’ oocytes and donor eggs have provided these
patients with new options. However, there is very little
known regarding the consequences of hormonal hyperstimulation of in vitro fertilization in breast carcinoma survivors, and further studies need to be done.
The ethical questions raised concerning this technology also are significant and are a topic of discussion.
We commend the work of Velentgas et al. and
their in-depth statistical analysis. Their findings are
consistent with those of other groups. The effect of
pregnancy on survival after successful treatment of
breast carcinoma has been studied by enough investigators and with adequate numbers to allow the formation of reasonable conclusions. First, pregnancy
does not appear to affect adversely the prognosis of
patients with Stage I or Stage II breast carcinoma. To
our knowledge the majority of studies show no difference in the overall and 5-year survival rates of patients
who become pregnant after breast carcinoma. In addition, neither the number of pregnancies, termination versus term pregnancies, nor the interval between
breast carcinoma treatment and subsequent pregnancy appear to alter patient outcome. Second, the
decision to conceive should be based on the prognosis
of the particular patient based on tumor type and
stage, not on the effect the pregnancy may have on the
breast carcinoma. Third, women who are diagnosed
with Stage IV disease with a 5-year survival rate of
0 –15% should not consider conception. Patients with
Stage III disease should consider deferring pregnancy
for at least 5 years after treatment. Finally, patients
with recurrent Stage I or Stage II tumors should not
contemplate conception because of the intensity of
treatment and the poor prognosis associated with
their diagnosis. Fourth, the potential for chemotherapy-induced ovarian failure secondary to adjuvant
treatment with alkylating agents may lead to infertility. Women with Stage I or Stage II tumors and a good
prognosis may be candidates for assisted reproductive
techniques, but the consequences of hormonal hyperstimulation may be adverse and need to be studied
further. Fifth, there may be a higher rate of spontaneous abortion in breast carcinoma survivors. This observation may be due to the effect of adjuvant chemotherapy and/or radiation therapy on ovarian function.
Finally, the decision to conceive after treatment for
breast carcinoma is a complicated one. It involves the
consideration of many factors, some medically related
and others psychologically related. Thorough counseling by a physician, oncology nurses, psychologists,
and other patients who have dealt with this issue may
be of utmost importance when a breast carcinoma
survivor considers pregnancy.
REFERENCES
1.
Velentgas P, Daling JR, Malone KE, Weiss NS, Williams MA,
Self SG, et al. Pregnancy after breast carcinoma: outcomes
and influence on mortality. Cancer 1999;85:2424 –32.
2. Harris JR, Morrow M, Bonadonna G. Cancer of the breast.
In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer:
principles of oncology. 4th edition. Philadelphia: J.B. Lippincott, 1993:1264 –332.
3. Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer
Res 1988;48:5615–23.
4. Janerich DT, Thompson WD, Mineau GP. Maternal pattern
of reproduction and risk of breast cancer in daughters: results from the Utah population database. J Natl Cancer Inst
1994;86:1634 –9.
5. Surbone A, Petrek J. Pregnancy after breast cancer. The
relationship of pregnancy to breast cancer development and
progression. Crit Rev Oncol Hematol 1998;27:169 –78.
6. Guinee VF, Olsson H, Moller T, Hess KR, Taylor SH, Fahey T,
et al. Effect of pregnancy on prognosis for young women
with breast cancer. Lancet 1994;343:1587–9.
7. Mignot L, Morvan F, Berdah J. Pregnancy after breast cancer: results of a case control study. Presse Med 1986;15:
1961– 4.
8. Ribiero G, Jones DA, Jones M. Carcinoma of the breast
associated with pregnancy. Br J Surg 1986;73:607–9.
9. Clark RM, Chua T. Breast cancer and pregnancy: the ultimate challenge. Clin Oncol (R Coll Radiol) 1989;1:11– 8.
10. Ariel I, Kempner R. The prognosis of patients who become
pregnant after mastectomy for breast cancer. Int Surg 1989;
74:185–7.
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CANCER June 1, 1999 / Volume 85 / Number 11
11. 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 –23.
12. Kromen N, Jensen MB, Melbye M, Wohlfahrt J, Mouridsen
HT. Should women be advised against pregnancy after
breast-cancer treatment? Lancet 1997;350:319 –22.
13. Harvey JC, Rosen PP, Ashikari H, Robbins GF, Kinne DW.
The effect of pregnancy on the prognosis of carcinoma of
the breast following radical mastectomy. Surg Gynecol Obstet 1981;153:723–5.
14. Clark FM, Reid JM. Carcinoma of the breast in pregnancy
and lactation. Int J Radiat Oncol Biol Phys 1978;4:693– 8.
15. Mignot L, Morvan F, Sarrazin D. Breast carcinoma and
subsequent pregnancy. Proc Am Soc Clin Oncol 1986;5:57.
16. Danforth DN. How subsequent pregnancy affects outcome in women with prior breast cancer. Oncology 1991;
523–30.
17. Mulvihill JJ, McKeen EA, Rosner F, Zarrabi MH. Pregnancy
outcome in cancer patients. Experience in a large cooperative group. Cancer 1987;60:1143–50.
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