Abstract
Background
An increasing number of young women are delaying childbearing; hence, more are diagnosed with breast cancer (bca) before having a family. No clear recommendations are currently available for counselling such a population on the safety of carrying a pregnancy during bca or becoming pregnant after treatment for bca.
Methods
Using a Web-based search of PubMed we reviewed the recent literature about bca and pregnancy. Our objective was to report outcomes for patients diagnosed with bca during pregnancy, comparing them with outcomes for non-pregnant women, and to evaluate prognosis in women diagnosed with and treated for bca who subsequently became pregnant.
Results
“Pregnancy and bca” should be divided into two entities. Pregnancy-associated bca tends to be more aggressive and advanced in stage at diagnosis than bca in control groups; hence, it has a poorer prognosis. With respect to pregnancy after bca, there is, despite the bias in reported studies and meta-analyses, no clear evidence for a different or worse disease outcome in bca patients who become pregnant after treatment compared with those who do not.
Conclusions
Pregnancy-associated bca should be treated as aggressively as and according to the standards applicable in nonpregnant women; pregnancy after bca does not jeopardize outcome. The guidelines addressing risks connected to pregnancy and bca lack a high level of evidence for better counselling young women about pregnancy considerations and preventing unnecessary abortions. Ideally, evidence from large prospective randomized trials would set better guidelines, and yet the complexity of such studies limits their feasibility.
Keywords: Breast cancer, pregnancy, outcomes, abortion
1. INTRODUCTION
With advances in local and systemic treatments, recurrence rates and risk of death secondary to breast cancer (bca) have been in continuous decline1. Breast cancer is among the malignancies most commonly encountered during pregnancy2,3: 0.2%–3.8% of cases are diagnosed during pregnancy and lactation4. The frequency increases with younger patient age: among women less than 30 years of age, 10%–20% of bca cases are diagnosed during pregnancy or within 1 year after delivery5. Since the early 2000s, women delaying childbearing has been an increasing trend6. More patients with bca inquire about fertility-related issues and whether a subsequent pregnancy might alter their risk of disease recurrence after adjuvant treatment7. Approximately 50% of women with a history of bca might wish for a subsequent pregnancy8, but only 4%–7% manage to become pregnant9. Potential explanations are damaged fertility and fear on the part of both the patient and her physician of a negative impact of pregnancy on the evolution of bca. Physicians have often assumed that pregnancy after bca increases the risk of cancer recurrence; they advise up to 35% of women who become pregnant after bca to have an abortion10,11. Understanding the risks of pregnancy during and after bca has become more important as more women delay childbearing. Few studies have looked at these issues, emphasizing the need to improve the quality of the available evidence so as to better counsel the women involved.
The objective of the present review was to report and discuss the guidelines currently used to treat women diagnosed with bca during pregnancy and to counsel women who seek to become pregnant after bca. This update to the current Canadian guidelines (last updated in 2002) sought to determine whether major changes in current daily practice were required.
2. METHODS
A manual and electronic Web-based search of med-line and PubMed retrieved all articles concerning bca and pregnancy published in the English language since the early 1990s, including cohort studies, reviews, mini-reviews, systematic reviews, and meta-analyses. All recent guidelines on pregnancy and bca reported and used by oncology societies were also retrieved. The search used combinations of these phrases or key words: “breast cancer during pregnancy,” “pregnancy after breast cancer,” “pregnancy following breast cancer,” “breast cancer after pregnancy,” “pregnancy associated breast cancer,” “breast carcinoma/cancer and pregnant women,” “childbearing after breast cancer/carcinoma.” We reviewed all articles addressing survival outcomes in patients who were diagnosed with bca during pregnancy or who became pregnant after being treated for bca. We focused mainly on any recently reported meta-analyses. The guidelines described and discussed in the present work came from the American Society of Clinical Oncology, the U.S. National Comprehensive Cancer Network, the European Society for Medical Oncology, and the Society of Obstetricians and Gynaecologists of Canada.
3. RESULTS
Our review identified two separate pregnancy and bca entities that should be approached and treated differently:
Women diagnosed with bca during pregnancy or within 1 year of delivery, known as pregnancy-associated bca (pabca)
Women who had been treated for early bca and were subsequently seeking to become pregnant, known as pregnancy after bca (pafbca)
Of 3459 articles initially retrieved, only fifty-eight studies, reviews, and meta-analyses met the search and eligibility criteria. We retained and analyzed all fifty-eight manuscripts that studied outcomes (survival) in patients diagnosed with bca during pregnancy and patients treated for bca who then became pregnant and compared those outcomes with outcomes in nonpregnant patients. We identified nineteen reviews, twenty studies of bca, and fifteen studies of pafbca. Most of the recent studies were retrospective; one large meta-analysis addressed bca, and three addressed pafbca. Figure 1 presents the prisma (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart for our search. Tables i and ii summarize all studies meeting our search criteria and reported in the literature since the early 1990s for bca and pafbca respectively.
TABLE I.
Reference | Pts (n) | Study type | Statistics | Results | Treatment (%) |
---|---|---|---|---|---|
Chang et al., 199412 | 21 | Retrospective | p=ns | No difference in survival | |
Guinee et al., 199413 | 407 | Retrospective |
hr: 3.26 95% ci: 1.81 to 5.87 p=0.0004 |
Worse survival in pregnant women | Surgery: 94 Radiation therapy: 58 Chemotherapy: 53 Hormonal therapy: 14 |
Ezzat et al., 199614 | 28 | Retrospective | p=0.86 | No difference in survival | Surgery: 100 Radiation therapy: 65 Chemotherapy: 57 |
Bonnier et al., 199715 | 154 | Retrospective | p=0.001 | Worse survival in pregnant women | Mastectomy: 41 Radiation therapy: 76.6 Chemotherapy: 63.6 Oophorectomy: 25.3 Tamoxifen: 17.5 |
Ibrahim et al., 200016 | 72 | Retrospective | p=0.79 | No difference in survival | Surgery: 65 Chemotherapy: 50 Radiation therapy: 86 |
Aziz et al., 200317 | 24 | Prospective | p>0.05 | No difference in survival | Surgery: 100 Radiation therapy: 21 Chemotherapy: 88 Hormonal therapy: 75 |
Zhang et al., 200318 | 88 | Retrospective | p=0.0536 | No difference in survival | |
Mathelin et al., 200819 | 40 | Prospective | p=0.0001 | Worse survival in pregnant women | Surgery: 100 Radiation therapy: 77.5 Chemotherapy: 82.5 Hormonal therapy: 45 |
Rodriguez et al., 200820 | 797 | Retrospective | p=0.002 | Worse survival in pregnant women | Surgery: 94 Radiation therapy: 39 Chemotherapy: 70 |
Beadle et al., 200921 | 208 | Retrospective | p=0.068 | No difference in survival | Surgery: 89 Radiation therapy: 46 Chemotherapy: 93 Hormonal therapy: 27 |
Halaska et al., 200922 | 32 | Retrospective | p=0.449 | No difference in survival | Surgery: 94 Chemotherapy: 100 Radiation therapy: 37.5 Hormonal therapy: 19 |
Makgasa et al., 200923 | 12 | Retrospective | p=0.005 (disease-free survival) | Worse survival in pregnant women | Surgery: 100 Chemotherapy: 58 |
Moreira et al., 201024 | 87 | Retrospective | 95% ci: 19.4 to 40.9 months p=0.005 |
Worse survival in pregnant women | Not reported |
Johansson et al., 201125 | 1110 | Retrospective |
hr: 3.8 95% ci: 2.4 to 5.9 |
Worse survival in pregnant women | Not reported |
Ali et al., 201226 | 40 | Retrospective | p=0.02 | Worse survival in pregnant women | Surgery: 95 Radiation therapy: 80 Chemotherapy: 90 |
Azim et al., 201227 | 65 | Retrospective |
hr: 2.6 95% ci: 1.0 to 6.5 |
Worse survival in pregnant women | Surgery: 100 Radiation therapy: 78.5 Adjuvant chemotherapy: 67.7 Neoadjuvant chemotherapy: 11 Hormonal therapy: 70.8 |
Murphy et al., 201228 | 99 | Retrospective | p=0.131 | No difference in survival | Surgery: 100 Radiation therapy: 49.5 Chemotherapy: 97 Hormonal therapy: 63 |
Amant et al., 201329 | 311 | Retrospective |
hr: 1.19 95% ci: 0.73 to 1.93 p=0.51 |
No difference in survival | Surgery: 93 Radiation therapy: 73 Chemotherapy: 99 Hormonal therapy: 41.5 |
Johansson et al., 201330 | 317 | Retrospective |
hr: 1.22 95% ci: 0.84 to 1.78 |
Worse survival in pregnant women | Not reported |
Litton et al., 201331 | 75 | Retrospective |
hr: 1.87 95% ci: 1.04 to 3.36 p=0.037 |
Better survival in pregnant women | Surgery: 96 Radiation therapy: 65 Neoadjuvant chemotherapy: 53 Adjuvant chemotherapy: 60 Hormonal therapy: 25 |
Pts = patients; ns= nonsignificant; hr= hazard ratio; ci= confidence interval.
TABLE II.
Reference | Pts (n) | Study type | Statistics | Results | Notes | Treatment (%) |
---|---|---|---|---|---|---|
Sankila et al., 199432 | 91 | Retrospective | Relative risk: 4.8 | Better survival in pregnant women | ||
Dow et al., 199433 | 23 | Retrospective | p=ns | No difference in survival | ||
von Schoultz et al., 199534 | 50 | Retrospective |
hr: 0.48 p=0.14 |
No difference in survival | Women pregnant before bca also studied | Not reported |
Lethaby et al., 199635 | 14 | Retrospective | p=ns | No difference in survival | Pregnant women with bca also studied | Not reported |
Gelber et al., 200110 | 94 | Retrospective | Risk ratio: 0.44 95% ci: 0.21 to 0.96 p=0.04 |
Better survival in pregnant women | Mastectomy: 68 Breast-conserving surgery: 22.6 Radiation therapy: 28 Chemotherapy: 59 |
|
Mueller et al., 200336 | 438 | Retrospective | Relative risk: 0.54 95% ci: 0.41 to 0.71 |
Better survival in pregnant women | Radiation therapy: 26 Chemotherapy: 31 |
|
Blakely et al., 200437 | 47 | Retrospective |
hr: 0.7 p=ns |
No difference in survival | Not reported | |
Ives et al., 200738 | 62 | Retrospective |
hr: 0.59 95% ci: 0.37 to 0.95 |
Better survival if conceiving more than 2 years from bca; no survival difference if conceiving more than 6 months from bca | Surgery: 100 Radiation therapy: 43 Chemotherapy: 41 |
|
Kroman et al., 200839 | 371 | Retrospective | Relative risk: 0.73 95% ci: 0.54 to 0.99 |
Better survival in pregnant women | Not reported | |
Rippy et al., 200940 | 18 | Retrospective | p=0.225 | No difference in survival | Not reported | |
Largillier et al., 200941 | Before: 105 After: 118 |
Retrospective | p<0.001 | No survival difference before pregnancy; better survival after pregnancy | Pregnant patients before and after bca | Pregnancy during preceding year: Surgery, 59; radiation therapy, 40; chemotherapy, 74 Pregnancy after treatment: Surgery, 67; radiation therapy, 49; chemotherapy, 65 |
Kranick et al., 201042 | 107 | Retrospective |
hr: 1.0 95% ci: 0.6 to 1.9 |
No difference in survival | Surgery: 100 Radiation therapy: 32.1 Chemotherapy: 38.7 Hormonal therapy: 2.8 |
|
Córdoba et al., 201243 | 18 | Retrospective | p=0.009 | Better survival for pregnant women | Women pregnant before bca also studied | Mastectomy: 61 Radiation therapy: 52.9 Chemotherapy: 89.9 Hormonal therapy: 38.9 |
Azim et al., 201344 | 333 | Retrospective | Disease-free survival: er+ hr, 0.91; 95% ci, 0.67 to 1.24; p=0.55; er– hr, 0.75; 95% ci, 0.51 to 1.08; p=0.12 Overall survival: hr, 0.72; 95% ci, 0.54 to 0.97; p=0.03 |
Same disease-free survival, better overall survival for pregnant women | Surgery: 100 Chemotherapy: 79 Hormonal therapy: 26 |
|
Valentini et al., 201345 | 128 | Retrospective |
hr: 0.76 95% ci: 0.31 to 1.91 p=0.56 |
No difference in survival | BRCA1/2 carriers, pregnancy during and after bca included | Surgery: 99.6 Radiation therapy: 52.8 Chemotherapy: 83.5 Tamoxifen: 17 |
Pts = patients; ns = nonsignificant; hr = hazard ratio; bca = breast cancer; ci = confidence interval; er+ = estrogen receptor–positive; er− = estrogen receptor–negative.
3.1. PABCa
3.1.1. Epidemiology and Clinicopathologic Features
The incidence of pabca is 1.3 in 10,000 births46. The disease is usually associated with an advanced-stage bulky primary tumour and nodal disease. It is diagnosed as stage ii–iii in 65%–90% of cases, in contrast to the 45%–66% for non-pregnancy-associated bca47,48. Diagnosis is almost always delayed (because of gestational physiologic alterations in the breast) and occurs at a younger age15,48. A delay of 1 month in diagnosis translates into a 0.9% increase in the odds of lymph node metastases49. Pregnancy-associated bca also has unfavourable biologic features related to poor prognostic outcome: high tumour grade, low hormone receptors, increased expression of her2 (human epidermal growth factor receptor 2), and high levels of Ki-67 nuclear antigen47,50.
3.1.2. Outcome and Management
In the early twentieth century, bca was considered to have such a poor prognosis that treatment was deemed futile. There was a persistent belief that bca accompanied by pregnancy portended poor survival51,52. Therapeutic abortion was a response to the belief that the hormonal milieu of pregnancy resulted in the poor outcome. Some studies indicate that prognosis in advanced-stage cancer is worse in the pregnancy-associated group than in a stage-matched nonpregnant group15,48, especially for women more than 35 years of age and for those diagnosed within 1 year postpartum20,21,24,28,53.
In a recent meta-analysis, the risk of death was more than 40% higher in women with pabca than in those with non-pabca54. However, although increased mortality was observed among women diagnosed with pabca, the difference became less pronounced after adjustment for age at diagnosis. Further adjustment for stage lowered the risk only slightly, suggesting that age, rather than stage, represents the principal driver of the increased mortality observed in women with pabca. This meta-analysis remains the largest work studying outcome in pabca and shows a clear trend of worse outcome especially for women diagnosed postpartum54.
Other studies show that prognosis in pabca is similar to that in bca unrelated to pregnancy when matched for age and disease stage15,21,55. Recently Amant et al.29 reported the largest cohort study to date on prognosis in pabca (311 women diagnosed and treated during pregnancy). After adjustment for known prognostic factors, those authors found no differences in disease-free (dfs) or overall survival (os) based on pregnancy at the time of the bca diagnosis. Multivariable methods confirmed that pregnancy was not a factor in recurrence or death risk for the pregnant population examined. Another recent study showed that patients treated with chemotherapy during pregnancy experience survival that is comparable to, if not better than, that in nonpregnant patients. The authors concluded that pabca patients in their second or third trimester should be appropriately treated using the established standard of care31.
Data from the literature are therefore not consistent, and the level of evidence from the reported results is low. The worse prognosis described for pabca might be only partly explained by the delay in diagnosis. The effect of pregnancy on prognosis because of an influence on the biology of the disease remains to be confirmed, especially given that pabca patients could potentially be undertreated.
3.2. PAFBCa
3.2.1. Preclinical Studies
Some biologic hypotheses have suggested a protective effect of pregnancy after bca. Preclinical models show that a high estrogen level after estrogen deprivation induces apoptosis in estrogen receptor (er)–positive bca cell lines56. In addition, fetal microchimerism has been suggested to act as an immunologic boost for patients previously exposed to tumour-associated antigens—for example, muc157.
3.2.2. Clinical Studies and Outcome Cohort Studies:
Several studies have addressed the safety of pregnancy after a bca diagnosis. Some suggested that pregnancy is associated with a better prognosis: that is, compared with women who did not become pregnant after a bca diagnosis, those who did become pregnant experienced a significant improvement in os. Mueller et al.36 found that pregnancy after bca treatment lowered the risk for death (relative risk: 0.54), which was statistically lower in women who were less than 35 years of age, who were of white ethnicity, and who had a tumour larger than 2 cm in size. In another study, an age- and stage-adjusted analysis revealed a lower relative risk for death (0.8) with pregnancy after bca treatment58. Blakely et al.37 showed that, in 370 women less than 35 years of age with bca, 47 became pregnant after adjuvant chemotherapy, and pregnancy did not increase the risk of recurrence or death. Ives et al.38 also found that pregnancy after bca treatment did not adversely affect survival, but that survival rates were better in women who delayed pregnancy for 24 months or more after the end of bca treatment.
Meta-analysis:
A large meta-analysis (fourteen studies) found that pregnancy after a bca diagnosis reduced the risk of death by 41%59. However, that reduced risk is likely confounded by a selection bias known as the “healthy mother effect”32. In a multicentre retrospective study, the same group studied the prognostic impact of pregnancy after bca by hormone receptor (er) status. Among patients with er-positive bca, those who became pregnant experienced the same dfs as a matched nonpregnant group. The same observation was reported when the analysis was restricted to er-negative patients or when it considered all patients regardless of er status. Furthermore, the pregnant group experienced better os, with no interaction by er status being observed44. There was no difference in dfs between the patients who became pregnant 2 years or more from their bca diagnosis and the matched group. However, those who became pregnant within 2 years of the bca diagnosis experienced a better dfs44. Another large meta-analysis addressed the same subject and tried to overcome the bias of the healthy mother effect. After considering the potential for such a bias in the matched controls, ten studies were eligible, and nine contained data appropriate for analysis. Overall survival was statistically higher among patients who became pregnant than among those who did not, showing that pregnancy occurring at least 10 months after a bca diagnosis does not jeopardize prognosis and might even confer a significant survival benefit60. The same results were also recently reported in a third meta-analysis studying the safety of pregnancy after surgical treatment for bca. No increase in the bca recurrence rate was observed, and a probable improvement in outcome (os) was also reported61.
Overall, the literature is reassuring and does not show a worse outcome for women with previously diagnosed and treated bca who seek to become pregnant afterward. Some data even suggest a better survival outcome. Those findings should bring comfort to physicians and to women with a previous bca diagnosis.
4. CURRENT INTERNATIONAL GUIDELINES
No current guideline is based on randomized prospective studies; hence, no level 1 evidence yet exists.
The National Comprehensive Cancer Network guideline does not recommend medical abortion for either situation (pabca and pafbca), especially for women with early bca. In case of metastasis, the treatment plan might be altered, influencing the patient’s decision about maintenance of pregnancy. Such alterations should be discussed in a multidisciplinary setting and also with the patient42,62.
The European Society for Medical Oncology also considers that evidence about any difference in prognosis between pregnant and nonpregnant women with bca is lacking, and it does not recommend pregnancy termination in that setting63,64 regardless of the er status of the tumour.
Recommendations from the Society of Obstetricians and Gynaecologists of Canada date to 2002. Because rates of survival tend to be the same in pabca and nonpregnant bca patients when the women are matched for age and stage, there is no strong evidence to recommend abortion for pabca. The available evidence for pafbca shows no detrimental effect on survival. With a low level of evidence, the society therefore recommends that women wait at least 3 years before attempting pregnancy (5 years if they have nodal involvement)65. Those timeframes might be unrealistic in terms of fertility maintenance after bca treatment.
Table iii summarizes the three foregoing guidelines.
TABLE III.
Guideline | Pregnancy-associated breast cancer | Pregnancy after breast cancer |
---|---|---|
esmo 201363,64 | No recommendation for abortion (lack of evidence) | No recommendation against pregnancya |
nccn 201442,62 | No recommendation for medical abortion (discussion in a multidisciplinary setting, discussion with patient) | No recommendation against pregnancy |
sogc 200265 | No recommendation for abortionb | No recommendation against pregnancy (no detrimental effect)c |
“Do not discourage pregnancy following breast cancer diagnosis irrespective of the [estrogen receptor] status.”
“In early pregnancy, the patient should be counseled regarding the effect of proposed therapy on the fetus and on overall maternal prognosis. Termination of pregnancy should be discussed, but the patient should be counseled that prognosis is not altered by termination of pregnancy.”
“Woman treated for [breast cancer], who wish to become pregnant should be counseled that pregnancy is possible and does not seem to be associated with a worse prognosis. However, they should be made aware that the evidence to support such advice is relatively poor.”
esmo= European Society for Medical Oncology; nccn= National Comprehensive Cancer Network; sogc= The Society of Obstetricians and Gynaecologists of Canada.
With respect to management and treatment, most guidelines recommend multidisciplinary decisions. Early diagnosis of pabca is crucial, and treatment, especially surgery, should not be delayed. Mastectomy and breast-conserving surgery are both acceptable options provided that the patient will, in the latter case, receive radiation treatment after delivery. Chemotherapy can be safely used during the 2nd and 3rd trimesters. Anthracyclines and cyclophosphamide can be given safely; data on the use of taxanes are limited. Radiation treatment, targeted therapies, and endocrine treatment should be initiated after delivery62,63,64.
5. DISCUSSION AND RECOMMENDATIONS
5.1. PABCa
Rates of pregnancy are usually lower in women who are cancer survivors than in the general female population; in women diagnosed with bca, the rate is nearly 70% lower64. As detailed earlier, the level of evidence is too low to conclude that outcomes are worse in patients with pabca than in nonpregnant patients diagnosed with bca of the same stage at the same age. In line with that understanding, most trials offered the study group (pregnant women) treatments (presented in Table i) that were not different from the treatments offered to the control group (nonpregnant women), showing that the pregnant patients were not undertreated. However, one meta-analysis reported worse outcomes for pregnant patients, especially the postpartum group, with significant heterogeneity between trials54. Hence, patients with pabca should be treated appropriately and as aggressively as non-pregnant patients. Choices and therapeutic sequences should be considered during a multidisciplinary meeting involving gynecologists, obstetricians, radiologists, oncologists, and pediatricians. No strong evidence supports a recommendation of pregnancy interruption or medical abortion in such cases.
5.2. PAFBCa
Pregnancy after bca can be considered safe in women with a history of bca. Some groups consider that a minimum period of 2 years after a bca diagnosis should pass before any attempt at pregnancy, both because of the reassuring results in patients who became pregnant more than 2 years after their bca diagnosis and because of the possible adverse effects of pregnancy and a high incidence of tumour recurrence during the first 2 years66. In addition, because of poorer prognosis and a higher recurrence rate, young women (<35 years of age) have been advised to wait at least 3 years and, in the presence of node-positive disease, at least 5 years before becoming pregnant67. The suggested delay might also allow patients to recover from chemotherapy-induced ovarian toxicity (even though there are no guarantees—especially given that, after chemotherapy, the ovarian reserve is diminished and more waiting time can be detrimental).
For patients with a history of er-positive breast cancer, 5–10 years of adjuvant hormonal therapy remains the current standard of care (10 years based on the attom and atlas trials68,69). Recommending that women complete their treatment period and then consider becoming pregnant presents a challenge for most patients, because their chances of pregnancy could be low after 5–10 years of tamoxifen70. A conflict always remains for women with er-positive disease who are willing to interrupt their endocrine treatment to become pregnant. These women should be counselled that interruption of hormonal therapy could be detrimental to their bca outcome. In women willing to consider the risk, interruption after 2–3 years of tamoxifen could be considered to allow for a pregnancy, with resumption of tamoxifen after delivery.
Going further, the type of treatment given did not differ for the study group (pafbca) compared with the control group (nonpregnant women) in most trials (Table ii). Consequently, counselling women against pregnancy remains unjustified. In addition, current data do not suggest an increased risk of birth defects or genetic diseases in infants delivered by women previously treated with chemotherapy71. However, increased incidences of birth complications (cesarean section, preterm birth, babies with low birth weight) are reported72. Close monitoring of pregnancy in women previously treated for cancer is therefore highly recommended.
More effort must be directed toward preserving the fertility of young women who are willing to consider pregnancy after completion of their chemotherapy. Patient preferences with respect to future fertility and the desire to have a biologic child should be critical factors during the decision-making process73. As emphasized in the recommendations from the American Society of Clinical Oncology, oncologists dealing with young women diagnosed with bca should be aware of infertility concerns and should address fertility issues early in the disease course74. Unfortunately, no strong evidence has as yet been developed to help clinicians advise patients about the optimal time to become pregnant after a bca diagnosis. Time of therapy completion, risk of relapse, and age and ovarian function of the patient should be taken into consideration. Postponing pregnancy for 2 years after diagnosis might be reasonable to allow for resumption of adequate ovarian function and to bypass the period associated with a relatively high risk of recurrence.
6. CONCLUSIONS
Given that no level 1 evidence has been developed addressing pregnancy and bca risk, young women who are diagnosed with bca during pregnancy or who are seeking to achieve pregnancy after bca treatment should receive a carefully coordinated multidisciplinary approach. Women diagnosed with bca during pregnancy should be treated as aggressively as their nonpregnant counterparts. The proscription against pregnancy after bca treatment because of concerns about cancer recurrence and death from bca is not supported by current data. Stronger and better guidelines supporting the conclusions and recommendations outlined here should ideally be developed from large randomized prospective trials conducted for validation, and yet we recognize the complexity of conducting such trials in this setting. To assess patient and pregnancy outcomes, a global prospective study by the Breast International Group and the North American Breast Cancer Group is prospectively collecting data about young women with early bca who desire pregnancy75.
7. CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.
8. REFERENCES
- 1.DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clin. 2011;61:409–18. doi: 10.3322/caac.20134. [DOI] [PubMed] [Google Scholar]
- 2.Smith LH, Danielsen B, Allen ME, Cress R. Cancer associated with obstetric delivery: results of linkage with the California cancer registry. Am J Obstet Gynecol. 2003;189:1128–35. doi: 10.1067/S0002-9378(03)00537-4. [DOI] [PubMed] [Google Scholar]
- 3.Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010;28:683–9. doi: 10.1200/JCO.2009.23.2801. [DOI] [PubMed] [Google Scholar]
- 4.Vinatier E, Merlot B, Poncelet E, Collinet P, Vinatier D. Breast cancer during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2009;147:9–14. doi: 10.1016/j.ejogrb.2009.06.030. [DOI] [PubMed] [Google Scholar]
- 5.Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36:237–49. doi: 10.1053/j.seminoncol.2009.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Matthews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief. 2009:1–8. [PubMed] [Google Scholar]
- 7.Azim HA, Jr, Peccatori FA, de Azambuja E, Piccart MJ. Motherhood after breast cancer: searching for la dolce vita. Expert Rev Anticancer Ther. 2011;11:287–98. doi: 10.1586/era.10.208. [DOI] [PubMed] [Google Scholar]
- 8.Letourneau JM, Smith JF, Ebbel EE, et al. Racial, socioeconomic, and demographic disparities in access to fertility preservation in young women diagnosed with cancer. Cancer. 2012;118:4579–88. doi: 10.1002/cncr.26649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Litton JK. Breast cancer and fertility. Curr Treat Options Oncol. 2012;13:137–45. doi: 10.1007/s11864-012-0185-5. [DOI] [PubMed] [Google Scholar]
- 10.Gelber S, Coates AS, Goldhirsch A, et al. on behalf of the International Breast Cancer Study Group Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer. J Clin Oncol. 2001;19:1671–5. doi: 10.1200/JCO.2001.19.6.1671. [DOI] [PubMed] [Google Scholar]
- 11.Ganz PA, Greendale GA, Petersen L, Kahn B, Bower JE. Breast cancer in younger women: reproductive and late health effects of treatment. J Clin Oncol. 2003;21:4184–93. doi: 10.1200/JCO.2003.04.196. [DOI] [PubMed] [Google Scholar]
- 12.Chang YT, Loong CC, Wang HC, Jwo SC, Lui WY. Breast cancer and pregnancy. Zhonghua Yi Xue Za Zhi (Taipei) 1994;54:223–9. [PubMed] [Google Scholar]
- 13.Guinee VF, Olsson H, Möller T, et al. Effect of pregnancy on prognosis for young women with breast cancer. Lancet. 1994;343:1587–9. doi: 10.1016/S0140-6736(94)93054-6. [DOI] [PubMed] [Google Scholar]
- 14.Ezzat A, Raja MA, Berry J, et al. Impact of pregnancy on non-metastatic breast cancer: a case control study. Clin Oncol (R Coll Radiol) 1996;8:367–70. doi: 10.1016/S0936-6555(96)80081-1. [DOI] [PubMed] [Google Scholar]
- 15.Bonnier P, Romain S, Dilhuydy JM, et al. Influence of pregnancy on the outcome of breast cancer: a case–control study. Societe Francaise de Senologie et de Pathologie Mammaire Study Group. Int J Cancer. 1997;72:720–7. doi: 10.1002/(SICI)1097-0215(19970904)72:5<720::AID-IJC3>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
- 16.Ibrahim EM, Ezzat AA, Baloush A, Hussain ZH, Mohammed GH. Pregnancy-associated breast cancer: a case–control study in a young population with a high-fertility rate. Med Oncol. 2000;17:293–300. doi: 10.1007/BF02782194. [DOI] [PubMed] [Google Scholar]
- 17.Aziz S, Pervez S, Khan S, et al. Case control study of novel prognostic markers and disease outcome in pregnancy/lactation-associated breast carcinoma. Pathol Res Pract. 2003;199:15–21. doi: 10.1078/0344-0338-00347. [DOI] [PubMed] [Google Scholar]
- 18.Zhang J, Liu G, Wu J, et al. Pregnancy-associated breast cancer: a case control and long-term follow-up study in China. J Exp Clin Cancer Res. 2003;22:23–7. [PubMed] [Google Scholar]
- 19.Mathelin C, Annane K, Treisser A, et al. Pregnancy and post-partum breast cancer: a prospective study. Anticancer Res. 2008;28:2447–52. [PubMed] [Google Scholar]
- 20.Rodriguez AO, Chew H, Cress R, et al. Evidence of poorer survival in pregnancy associated breast cancer. Obstet Gynecol. 2008;112:71–8. doi: 10.1097/AOG.0b013e31817c4ebc. [DOI] [PubMed] [Google Scholar]
- 21.Beadle BM, Woodward WA, Middleton LP, et al. The impact of pregnancy on breast cancer outcomes in women <or= 35 years. Cancer. 2009;115:1174–84. doi: 10.1002/cncr.24165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Halaska MJ, Pentheroudakis G, Strnad P, et al. Presentation, management and outcome of 32 patients with pregnancy-associated breast cancer: a matched controlled study. Breast J. 2009;15:461–7. doi: 10.1111/j.1524-4741.2009.00760.x. [DOI] [PubMed] [Google Scholar]
- 23.Makgasa M, Prichard RS, Malone C, Kerin MJ. Pregnancy associated breast cancer. Ir Med J. 2009;102:314–17. [PubMed] [Google Scholar]
- 24.Moreira WB, Brandao EC, Soares AN, Lucena CE, Antunes CM. Prognosis for patients diagnosed with pregnancy-associated breast cancer: a paired case–control study. Sao Paulo Med J. 2010;128:119–24. doi: 10.1590/S1516-31802010000300003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Johansson AL, Andersson TM, Hsieh CC, Cnattingius S, Lambe M. Increased mortality in women with breast cancer detected during pregnancy and different periods postpartum. Cancer Epidemiol Biomarkers Prev. 2011;20:1865–72. doi: 10.1158/1055-9965.EPI-11-0515. [DOI] [PubMed] [Google Scholar]
- 26.Ali SA, Gupta S, Sehgal R, Vogel V. Survival outcomes in pregnancy associated breast cancer: a retrospective case control study. Breast J. 2012;18:139–44. doi: 10.1111/j.1524-4741.2011.01201.x. [DOI] [PubMed] [Google Scholar]
- 27.Azim HA, Jr, Botteri E, Renne G, et al. The biological features and prognosis of breast cancer diagnosed during pregnancy: a case–control study. Acta Oncol. 2012;51:653–61. doi: 10.3109/0284186X.2011.636069. [DOI] [PubMed] [Google Scholar]
- 28.Murphy CG, Mallam D, Stein S, et al. Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer. Cancer. 2012;118:3254–9. doi: 10.1002/cncr.26654. [DOI] [PubMed] [Google Scholar]
- 29.Amant F, Von Minckwitz G, Han SN, et al. Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study. J Clin Oncol. 2013;31:2532–9. doi: 10.1200/JCO.2012.45.6335. [DOI] [PubMed] [Google Scholar]
- 30.Johansson AL, Andersson TM, Hsieh CC, et al. Stage at diagnosis and mortality in women with pregnancy-associated breast cancer (bc) Breast Cancer Res Treat. 2013;139:183–92. doi: 10.1007/s10549-013-2522-1. [DOI] [PubMed] [Google Scholar]
- 31.Litton JK, Warneke CL, Hahn KM, et al. Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer. Oncologist. 2013;18:369–76. doi: 10.1634/theoncologist.2012-0340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Sankila R, Heinävaara S, Hakulinen T. Survival of breast cancer patients after subsequent term pregnancy: “healthy mother effect”. Am J Obstet Gynecol. 1994;170:818–23. doi: 10.1016/S0002-9378(94)70290-X. [DOI] [PubMed] [Google Scholar]
- 33.Dow KH, Harris JR, Roy C. Pregnancy after breast-conserving surgery and radiation therapy for breast cancer. J Natl Cancer Inst Monogr. 1994:131–7. [PubMed] [Google Scholar]
- 34.von Schoultz E, Johansson H, Wilking N, Rutqvist LE. Influence of prior and subsequent pregnancy on breast cancer prognosis. J Clin Oncol. 1995;13:430–4. doi: 10.1200/JCO.1995.13.2.430. [DOI] [PubMed] [Google Scholar]
- 35.Lethaby AE, O’Neill MA, Mason BH, Holdaway IM, Harvey VJ. Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group. Int J Cancer. 1996;67:751–5. doi: 10.1002/(SICI)1097-0215(19960917)67:6<751::AID-IJC1>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- 36.Mueller BA, Simon MS, Deapen D, Kamineni A, Malone KE, Daling JR. Childbearing and survival after breast carcinoma in young women. Cancer. 2003;98:1131–40. doi: 10.1002/cncr.11634. [DOI] [PubMed] [Google Scholar]
- 37.Blakely LJ, Buzdar AU, Lozada JA, et al. Effects of pregnancy after treatment for breast carcinoma on survival and risk of recurrence. Cancer. 2004;100:465–9. doi: 10.1002/cncr.11929. [DOI] [PubMed] [Google Scholar]
- 38.Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ. 2007;334:194. doi: 10.1136/bmj.39035.667176.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Kroman N, Jensen MB, Wohlfahrt J, Ejlertsen B, on behalf of the Danish Breast Cancer Cooperative Group Pregnancy after treatment of breast cancer—a population-based study on behalf of Danish Breast Cancer Cooperative Group. Acta Oncol. 2008;47:545–9. doi: 10.1080/02841860801935491. [DOI] [PubMed] [Google Scholar]
- 40.Rippy EE, Karat IF, Kissin MW. Pregnancy after breast cancer: the importance of active counselling and planning. Breast. 2009;18:345–50. doi: 10.1016/j.breast.2009.08.003. [DOI] [PubMed] [Google Scholar]
- 41.Largillier R, Savignoni A, Gligorov J, et al. on behalf of the get(n)a group Prognostic role of pregnancy occurring before or after treatment of early breast cancer patients aged <35 years: a get(n)a working group analysis. Cancer. 2009;115:5155–65. doi: 10.1002/cncr.24608. [DOI] [PubMed] [Google Scholar]
- 42.Kranick JA, Schaefer C, Rowell S, et al. Is pregnancy after breast cancer safe? Breast J. 2010;16:404–11. doi: 10.1111/j.1524-4741.2010.00939.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Córdoba O, Bellet M, Vidal X, et al. Pregnancy after treatment of breast cancer in young women does not adversely affect the prognosis. Breast. 2012;21:272–5. doi: 10.1016/j.breast.2011.10.001. [DOI] [PubMed] [Google Scholar]
- 44.Azim HA, Jr, Kroman N, Paesmans M, et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J Clin Oncol. 2013;31:73–9. doi: 10.1200/JCO.2012.44.2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Valentini A, Lubinski J, Byrski T, et al. on behalf of the Hereditary Breast Cancer Clinical Study Group The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation. Breast Cancer Res Treat. 2013;142:177–85. doi: 10.1007/s10549-013-2729-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Smith LH, Dalrymple JL, Leiserowitz GS, Danielsen B, Gilbert WM. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol. 2001;184:1504–12. doi: 10.1067/mob.2001.114867. [DOI] [PubMed] [Google Scholar]
- 47.Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer. 2003;98:1055–60. doi: 10.1002/cncr.11614. [DOI] [PubMed] [Google Scholar]
- 48.Ishida T, Yokoe T, Kasumi F, et al. Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: analysis of case–control study in Japan. Jpn J Cancer Res. 1992;83:1143–9. doi: 10.1111/j.1349-7006.1992.tb02737.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Nettleton J, Long J, Kuban D, Wu R, Shaefffer J, El-Mahdi A. Breast cancer during pregnancy: quantifying the risk of treatment delay. Obstet Gynecol. 1996;87:414–18. doi: 10.1016/0029-7844(95)00470-X. [DOI] [PubMed] [Google Scholar]
- 50.Reed W, Hannisdal E, Skovlund E, Thoresen S, Lilleng P, Nesland JM. Pregnancy and breast cancer: a population-based study. Virchows Arch. 2003;443:44–50. doi: 10.1007/s00428-003-0817-z. [DOI] [PubMed] [Google Scholar]
- 51.Jensen EV, Descombre ER, Kawashima T, Suzuki T, Kyser K, Jungblut PW. Estrogen-binding substances of target tissues. Science. 1967;158:529–30. doi: 10.1126/science.158.3800.529-c. [DOI] [PubMed] [Google Scholar]
- 52.McGuire WL. Steroid hormone receptors and disease: breast cancer. Proc Soc Exp Biol Med. 1979;162:22–5. doi: 10.3181/00379727-162-40610. [DOI] [PubMed] [Google Scholar]
- 53.Stensheim H, Moller B, van Dijk T, Fossa SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27:45–51. doi: 10.1200/JCO.2008.17.4110. [DOI] [PubMed] [Google Scholar]
- 54.Azim HA, Jr, Santoro L, Russell–Edu W, Pentheroudakis G, Pavlidis N, Peccatori FA. Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies. Cancer Treat Rev. 2012;38:834–42. doi: 10.1016/j.ctrv.2012.06.004. [DOI] [PubMed] [Google Scholar]
- 55.Cardonick E, Dougherty R, Grana G, Gilmandyar D, Ghaffar S, Usmani A. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16:76–82. doi: 10.1097/PPO.0b013e3181ce46f9. [DOI] [PubMed] [Google Scholar]
- 56.Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17β-estradiol. J Natl Cancer Inst. 2001;93:1714–23. doi: 10.1093/jnci/93.22.1714. [DOI] [PubMed] [Google Scholar]
- 57.Kamper–Jørgensen M, Biggar RJ, Tjønneland A, et al. Opposite effects of microchimerism on breast and colon cancer. Eur J Cancer. 2012;48:2227–35. doi: 10.1016/j.ejca.2012.02.006. [DOI] [PubMed] [Google Scholar]
- 58.Velentgas P, Daling JR, Malone KE, et al. Pregnancy after breast carcinoma: outcomes and influence on mortality. Cancer. 1999;85:2424–32. doi: 10.1002/(SICI)1097-0142(19990601)85:11<2424::AID-CNCR17>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
- 59.Azim HA, Jr, Santoro L, Pavlidis N, et al. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74–83. doi: 10.1016/j.ejca.2010.09.007. [DOI] [PubMed] [Google Scholar]
- 60.Valachis A, Tsali L, Pesce LL, et al. Safety of pregnancy after primary breast carcinoma in young women: a meta-analysis to overcome bias of healthy mother effect studies. Obstet Gynecol Surv. 2010;65:786–93. doi: 10.1097/OGX.0b013e31821285bf. [DOI] [PubMed] [Google Scholar]
- 61.Luo M, Zeng J, Li F, He L, Li T. Safety of pregnancy after surgical treatment for breast cancer: a meta-analysis. Int J Gynecol Cancer. 2014;24:1366–72. doi: 10.1097/IGC.0000000000000242. [DOI] [PubMed] [Google Scholar]
- 62.National Comprehensive Cancer Network (nccn) NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington PA: NCCN; 2014. Ver 32014. [Current version available online at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (free registration required); cited December 22, 2014] [Google Scholar]
- 63.Pentheroudakis R, Orecchia R, Hoekstra HJ, Pavlidis N, on behalf of the esmo guidelines working group Cancer, fertility and pregnancy: esmo clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(suppl 5):v266–73. doi: 10.1093/annonc/mdq198. [DOI] [PubMed] [Google Scholar]
- 64.Peccatori FA, Azim HA, Jr, Orecchia R, et al. on behalf of the esmo guidelines working group Cancer, pregnancy and fertility: esmo clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi160–70. doi: 10.1093/annonc/mdt199. [DOI] [PubMed] [Google Scholar]
- 65.Helewa M, Lévesque P, Provencher D, Lea RH, Rosolowich V, Shapiro HM, on behalf of the Breast Disease Committee and Executive Committee and Council. Society of Obstetricians and Gynaecologists of Canada Breast cancer, pregnancy, and breastfeeding. J Obstet Gynaecol Can. 2002;24:164–84. [PubMed] [Google Scholar]
- 66.Pagani O, Price KN, Gelber RD, et al. on behalf of the International Breast Cancer Study Group Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century. Breast Cancer Res Treat. 2009;117:319–24. doi: 10.1007/s10549-008-0282-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Averette HE, Mirhashemi R, Moffat FL. Pregnancy after breast carcinoma: the ultimate medical challenge. Cancer. 1999;85:2301–4. doi: 10.1002/(SICI)1097-0142(19990601)85:11<2301::AID-CNCR1>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
- 68.Davies C, Pan HC, Godwin J, et al. on behalf of the Adjuvant Tamoxifen: Longer Against Shorter (atlas) collaborative group Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen-receptor positive breast cancer: atlas, a randomised trial. Lancet. 2013;381:805–16. doi: 10.1016/S0140-6736(12)61963-1. [Erratum in: Lancet 2013;381:804] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Gray RG, Rea D, Handley K, et al. Attom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6953 women with early breast cancer [abstract 05] J Clin Oncol. 2013;31 doi: 10.1200/JCO.2012.47.5301. [Available online at: http://meetinglibrary.asco.org/content/112995-132; cited December 22, 2014] [DOI] [Google Scholar]
- 70.Pagani O, Partridge A, Korde L, et al. on behalf of the Breast International Group. North American Breast Cancer Group Endocrine Working Group Pregnancy after breast cancer: if you wish, ma’am. Breast Cancer Res Treat. 2011;129:309–17. doi: 10.1007/s10549-011-1643-7. [DOI] [PubMed] [Google Scholar]
- 71.Winther JF, Olsen JH, Wu H, et al. Genetic disease in the children of Danish survivors of childhood and adolescent cancer. J Clin Oncol. 2012;30:27–33. doi: 10.1200/JCO.2011.35.0504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Dalberg K, Eriksson J, Holmberg L. Birth outcome in women with previously treated breast cancer—a population-based cohort study from Sweden. PLoS Med. 2006;3:e336. doi: 10.1371/journal.pmed.0030336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with breast cancer. Breast. 2007;16(suppl 2):S175–81. doi: 10.1016/j.breast.2007.07.029. [DOI] [PubMed] [Google Scholar]
- 74.Loren AW, Mangu PB, Beck LN, et al. on behalf of the American Society of Clinical Oncology Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2500–10. doi: 10.1200/JCO.2013.49.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during pregnancy. International recommendations from an expert meeting. Cancer. 2006;106:237–46. doi: 10.1002/cncr.21610. [DOI] [PubMed] [Google Scholar]