Pregnancy after breast cancer. A comprehensive review

Pregnancy after breast cancer treatment has become an important issue since many young breast cancer patients have not completed their family. Generally, these patients should not be discouraged to become pregnant when they want to, since published data suggest no adverse effect of pregnancy on survival. As fertility may be impaired by chemotherapy, different fertility preserving strategies have been developed. Births seem to sustain no adverse effects, while breastfeeding appears to be feasible and safe. J. Surg. Oncol. 2010; 101:534–542. © 2010 Wiley‐Liss, Inc.     

Telomere length,oxidative damage,antioxidants and breast cancer risk

Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell DNA telomere length on breast cancer risk, and examined whether urinary 15‐F₂‐isoprostanes (15‐F_2t‐IsoP) and 8‐oxo‐7,8‐dihydrodeoxyguanosine (8‐oxodG) or dietary antioxidant intake modified the relationship between telomere length and breast cancer risk. A population‐based case–control study—the Long Island Breast Cancer Study Project—was conducted among 1,067 cases and 1,110 controls. Telomere length was assessed by quantitative PCR. Overall, the mean levels of telomere length (T/S ratio), 15‐F_2t‐IsoP and 8‐oxodG were not significantly different between cases and controls. Among premenopausal women only, carrying shorter telomeres (Q3 and Q4), as compared with the longest (Q1), was associated with significantly increased breast cancer risk. Age‐adjusted OR and 95% CI were 1.71 (1.10–2.67) and 1.61 (1.05–2.45). The 5‐F_2t‐IsoP and 8‐oxodG biomarkers did not modify the telomere–breast cancer association. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of β‐carotene, vitamin C or E intake [OR (95% CI) = 1.48 (1.08–2.03), 1.39 (1.01–1.92) and 1.57 (1.14–2.18), respectively], although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (p_trend = 0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among premenopausal women or women with low dietary intake of antioxidants or antioxidant supplements. © 2008 Wiley‐Liss, Inc.     

The impact of pregnancy on breast cancer outcomes in women ≤35 years

BACKGROUND:

Some evidence suggests that women with pregnancy‐associated breast cancers (PABC) have a worse outcome compared with historical controls. However, young age is a worse prognostic factor independently, and women with PABC tend to be young. The purpose of the current study was to compare locoregional recurrence (LRR), distant metastases (DM), and overall survival (OS) in young patients with PABC and non‐PABC.

METHODS:

Data for 668 breast cancers in 652 patients aged ≤35 years were retrospectively reviewed. One hundred four breast cancers (15.6%) were pregnancy‐associated; 51 cancers developed during pregnancy and 53 within 1 year after pregnancy.

RESULTS:

The median follow‐up for all living patients was 114 months. Patients who developed PABC had more advanced T classification, N classification, and stage group (all P < .04) compared with patients with non‐PABC. Patients with PABC had no statistically significant differences in 10‐year rates of LRR (23.4% vs 19.2%; P = .47), DM (45.1% vs 38.9%; P = .40), or OS (64.6% vs 64.8%; P = .60) compared with patients with non‐PABC. For those patients who developed breast cancer during pregnancy, any treatment intervention during pregnancy provided a trend toward improved OS compared with delaying evaluation and treatment until after delivery (78.7% vs 44.7%; P = .068).

CONCLUSIONS:

Young patients with PABC had no statistically significant differences in LRR, DM, or OS compared with those with non‐PABC; however, pregnancy contributed to a delay in breast cancer diagnosis, evaluation, and treatment. Primary care and reproductive physicians should be aggressive in the workup of breast symptoms in the pregnant population to expedite diagnosis and allow multidisciplinary treatment. Cancer 2009. © 2009 American Cancer Society.     

Leg length, sitting height and postmenopausal breast cancer risk

Background:

Tallness has consistently been associated with an increased risk of breast cancer. We investigated the association further by decomposing height into leg length and sitting height.

Methods:

From the prospective Danish cohort ‘Diet, Cancer and Health'', 23 864 postmenopausal women enrolled during 1993–1997 were followed for a diagnosis of breast cancer in the Danish Cancer Registry through 2009.

Results:

The incidence rate ratios for breast cancer were 1.11 (95% CI=1.06–1.16) for each 5 cm increase in total height and 1.09 (95% CI=1.01–1.17) and 1.14 (95% CI=1.04–1.25) for each 5 cm increase in leg length and sitting height, respectively. There was no statistical significant difference between the associations for leg length and sitting height (P=0.47).

Conclusion:

Leg length does not seem to be more strongly associated with breast cancer among postmenopausal women than sitting height.     

The impact of bilateral breast cancer on the prognosis of breast cancer: a comparative study with unilateral breast cancer

BACKGROUND: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We assessed the impact of synchronous and metachronous bilateral breast cancer on the prognosis compared with unilateral breast cancer. METHODS: Between January 1, 1960 and December 31, 2001, 1,214 women were treated for primary operable breast cancers. Thirteen (1.1%) had synchronous bilateral breast cancer; 33 (2.7%) had a metachronous contralateral breast cancer. We compared age at operation, menopausal status, clinical stage, tumor size and histology, lymph node status, hormone receptor status, and use of adjuvant chemotherapy or hormone therapy, and we analyzed the impact of these factors on recurrence and survival in the 46 patients with bilateral breast cancer and the 1,168 patients with unilateral breast cancer. RESULTS: The 5-and 10-year disease-free survival rates, respectively, were 65% and 65% in metachronous cases, 85.7% and 64.3% in synchronous cases, and 77.9% and 72.1% in unilateral cases. There was no significant difference in overall survival among the three groups. On multivariate analysis, metachronous bilaterality, tumor size, lymph node status and adjuvant hormone therapy were each independent risk factors for recurrence, whereas bilaterality of breast cancer did not influence overall survival. CONCLUSIONS: Our data suggest that metachronous bilateral breast cancer is associated with shorter disease-free survival than synchronous bilateral or unilateral breast cancer, although overall survival does not differ among the 3 groups. Patients with metachronous bilateral breast cancer should be followed particularly closely in order to detect recurrence early and maximize quality of life.     

Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation

High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.     

Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS+epithelial cells or total epithelial cells was 69±16% (n=50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62±20 (n=40), compared to 12±9 (n=40) in samples of grade III carcinomas (P<0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n=4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumors metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.     

Lactation following conservation surgery and radiotherapy for breast cancer

A 38-year-old woman with early stage invasive breast cancer was treated with wide excision of the tumor, axillary lymph node dissection, and breast irradiation. Three years later, she gave birth to a normal baby. She attempted breast feeding and had full lactation from the untreated breast. The irradiated breast underwent only minor changes during pregnancy and postpartum but produced small amounts of colostrum and milk for 2 weeks postpartum. There are only a few reports of lactation after breast irradiation. These cases are reviewed, and possible factors affecting breast function after radiotherapy are discussed. Because of scant information available regarding its safety for the infant, nursing from the irradiated breast is not recommended.     

Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel

The focus of this paper is a case study of a woman in the first trimester of pregnancy who presented with metastatic breast cancer. The bony spread of the metastases was rapid and it was necessary to treat the patient as soon as possible after the period of organogenesis (days 18–60 of human gestation). This stage is the phase of greatest sensitivity of teratogens and the malformations are observed most often. Yet, the choice of third-line chemotherapy was difficult because of anthracycline-resistant metastatic breast cancer. The world literature reported cytotoxic combinated regimens as the standard of care for the management of the metastases. The development of new antitumoral strategies with less toxicity and their encouraging results led us to the approval of docetaxel for the treatment of the patient even though it had never been tested in pregnancy. Docetaxel is a potent inhibitor of microtubule depolymerization and has a unique ability to alter certain classes of microtubules. The monochemotherapy was administered once every 3 weeks for a total of three cycles until 30 weeks of gestation. During the 32nd week of pregnancy the patient delivered a female infant whose birthweight and Apgar score were normal. The infant did not have any anomalies. The woman finished her treatment in puerperium and she received three cycles of docetaxel. The patient has been receiving vinorelbine (one cycle every 2 weeks) for 2 years; her last follow-up was good and showed that the progression of the metastases had stopped. The daughter's psychophysical development was normal.     

Diagnosis and Treatment Experience of 14 Cases of Breast Cancer Associated with Pregnancy or Lactation

Objective： To explore the diagnosis and treatment experience of breast cancer associated with pregnancy or lactation. Methods： From January 1990 to December 2005, 14 cases with breast cancer associated with pregnancy or lactation were analyzed retrospectively （TNM stage Ⅱ, 2 cases; stage Ⅲ, 11 cases; stage Ⅳ, 1 case）. Diagnosis was established by fine needle aspiration biopsy primarily or routine pathological method if necessary. Abortion was used for discontinuation of pregnancy in 1 case with early pregnancy and 1 case with meddle pregnancy. 2 patients with late pregnancy received cesarean section, 10patients of breast cancer associated with lactation received multidisciplinary and-tumor treatment after discontinuation of lactation. Results： Diagnosis was confirmed by fine noodle aspiration biopsy in 9 cases and by secondary routine pathological method in the other 5 cases, 12 cases were followed up, 1 case of stage Ⅳ died of metastasis 5 months after diagnosis. 3-, 5-year survival rates in 10 cases of stage Ⅲ were 66% and 30% respectively. One case remained alive without recurrence for 8 years up to now. Conclusion： A thorough breast examination is necessary at the first antenatal visit physicians should aggressively pursue work-up in women with a palpable breast tass. In the patients during the second and third trimness, the various modalities available for treatment inholding abortion and their risks and beneath modalities available for treatment including abortion and their risks and benefits must be discussed openly with patients and their families.     

Pregnancy complications and subsequent breast cancer risk in the mother: a Nordic population‐based case–control study

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population‐based case–control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967–2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78–0.97), gestational hypertension (OR 0.90; 95% CI 0.86–0.93) and preeclampsia (OR 0.91; 95% CI 0.88–0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98–1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation.     

Comparison of age at first full-term pregnancy between women with breast cancer and women with benign breast diseases

Benign breast diseases have a broadly similar risk profile to that of breast cancer, possibly reflecting a similar underlying endocrine milieu. We have hypothesized that a crucial distinction between breast cancer and benign breast diseases is that mammary gland terminal differentiation has not been successfully accomplished among women who tend to develop breast cancer. From October 2001 to December 2002, information concerning breast cancer risk factors and sociodemographic characteristics was collected from 174 women with breast cancer and 116 women with benign breast diseases, all 30 years old or older, who were histologically diagnosed at a major prevention center in Athens, Greece. Among the examined breast cancer risk factors, only age at first full-term pregnancy was significantly associated with the odds of having breast cancer rather than benign breast disease, and the association was evident among premenopausal [odds ratio (OR) per 5 years = 1.76, 95% confidence interval (CI) 1.10-2.93] and postmenopausal (OR = 2.10, 95% CI 1.16-3.71) women, as well as among all women (OR = 1.93, 95% CI 1.34-2.70). There was no evidence that any of the remaining breast cancer risk factors could discriminate between breast cancer and benign breast diseases. We conclude that early age at first pregnancy may convey substantial protection against breast cancer risk among women with benign breast diseases, probably operating through induction of terminal differentiation of mammary gland cells. The finding is accentuated by the fact that women with benign breast diseases are already at a relatively high risk for breast cancer.     

Pre-eclampsia in pregnancy and subsequent risk for breast cancer

Women who experience pre-eclampsia or hypertension during pregnancy may have a reduced risk for breast cancer later in life. The evidence is based on case-control studies, and here we report the results of a cohort study exploring the link between pre-eclampsia and gestational hypertension diagnosed in the first pregnancy and subsequent risk for breast cancer. We combined information from the Medical Birth Registry and the Cancer Registry in Norway, which are both nation-wide. Between 1967, when the birth registry was established, and 1998, 694 657 women were recorded with a first birth, and classified according to whether pre-eclampsia and/or hypertension was diagnosed in the first pregnancy. Linkage to the Norwegian Cancer Registry identified 5474 new cases of breast cancer diagnosed subsequently to their first delivery. Compared to other parous women, women with pre-eclampsia and/or hypertension diagnosed in their first pregnancy had 19% lower risk (95% confidence interval, 9 to 29%) for breast cancer, after adjustment for attained age, calendar period of diagnosis, age at first birth, and parity. This result was similar for term and preterm deliveries, across the range of offspring birth weight, and for pre- and postmenopausal women. These results suggest that the pathophysiology surrounding pre-eclampsia and gestational hypertension plays an important role in breast cancer etiology. A better understanding of the underlying processes could provide an insight into the pathogenesis of breast cancer.     

Smoking during pregnancy and breast cancer risk in very young women (United States)

Objective: To evaluate the association of smoking during a woman's first pregnancy, a period of pronounced growth and differentiation of mammary tissue, and her subsequent breast cancer risk. Methods: In this matched case–control study, we used linked birth certificate and tumor registry data from the New York State Health Department. Cases were 319 women aged 26–45 who were diagnosed with breast cancer in New York State between 1989 and 1995 and who completed a first pregnancy in New York State after 1987 at least one year prior to diagnosis of cancer. Controls were 768 primiparous women matched to cases on county of residence and delivery date. Information on prenatal smoking and other factors characterizing the woman's first pregnancy was obtained from the pregnancy record of each subject, and the association of these factors to breast cancer risk was assessed using conditional logistic regression. Results: Smoking during pregnancy was associated with increased risk for breast cancer (crude OR = 2.7, 95% confidence interval (CI): 1.1–6.3). Adjustment for maternal age, subject age, race, and education strengthened this association (OR = 4.8, CI 1.6–14.6). Conclusions: These findings suggest that cigarette smoking during a woman's first pregnancy may increase her risk for early-onset breast cancer.     

The impact of having a sister diagnosed with breast cancer on cancer‐related distress and breast cancer risk perception

BACKGROUND:

A family history of breast cancer has been shown to affect psychosocial functioning. However, the majority of research has focused on the daughters of patients with breast cancer and families with multiple relatives with the disease. The purpose of the current study was to examine cancer‐related distress and breast cancer risk perception, and further examine the predictors of these outcomes, in the sisters of newly diagnosed patients with breast cancer without a previous family history of the disease.

METHODS:

Sisters of newly diagnosed index breast cancer patients were identified and asked to complete a study‐specific questionnaire (demographics and cancer risk perception) and the Impact of Events Scale. Pathological information was abstracted from the medical chart for the index breast cancer patients.

RESULTS:

A total of 205 sisters completed the questionnaires. The mean time between breast cancer diagnosis and the sisters' completion of the questionnaire was 9.8 months. Approximately one‐half of the women scored in the moderate or severe distress range. The most significant predictor of cancer‐related distress was perceived lifetime breast cancer risk (P = .04). Women with a lifetime risk of breast cancer > 20% were more than twice as likely to have moderate or severe distress compared with those with a lifetime risk of < 20%.

CONCLUSIONS:

Cancer‐related distress is high in the sisters of newly diagnosed patients with breast cancer in whom there is no other family history of breast cancer. Specifically, women with a perceived lifetime risk of breast cancer of > 20% experienced the highest levels of distress. Future interventions that target this group should be considered. Cancer 2013. © 2013 American Cancer Society.     

Motherhood after breast cancer: searching for la dolce vita

Advances in the field of adjuvant therapy in breast cancer have led to significant improvements in breast cancer survival. This has resulted in a progressive decline in breast cancer-related mortality, such that in 2010 there were estimated to be 400,000 breast cancer survivors under the age of 40 in the USA. Hence, enquiry into the feasibility of fertility preservation, subsequent pregnancy and breastfeeding is increasingly encountered. Fertility counseling remains suboptimal in breast cancer clinics, and there is a wide perception that pregnancy could worsen the prognosis of young breast cancer survivors, despite the lack of evidence supporting this notion. In addition, fertility preservation by means of embryo or oocyte cryopreservation requires ovarian stimulation, which is associated with a significant rise in estradiol levels and might delay initiation of therapy. All these factors, and others, have influenced the quality of fertility counseling offered to young breast cancer patients. In this article, we will critically analyze the available clinical and biological evidence on the safety and feasibility of pregnancy and breastfeeding following breast cancer. In addition, we will discuss the different fertility-preservation techniques available for these patients.     

Insulin and related factors in premenopausal breast cancer risk

Background: Insulin and insulin-like growth factor I (IGF-I) are important mitogens in vitro and in vivo. It has been hypothesized that these factors may play an important role in the development of breast cancer. Methods: A case-control study comparing plasma insulin levels in 99 premenopausal women with newly diagnosed node-negative invasive carcinoma of the breast and 99 age-matched controls with incident biopsied non-proliferative breast disease (NP) was conducted. Women with known diabetes were excluded. Results: For the entire study group, mean age was 42.6 ± 5.1 years and mean weight was 62.9 ± 10.3 kg. After adjustment for age and weight, elevated insulin levels were significantly associated with breast cancer, Odds Ratio (OR) for women in the highest insulin quintile versus the lowest quintile=2.83 (95% Confidence Interval [CI] 1.22–6.58). There were no statistically significant differences between cases and controls for IGF-I and IGFBP-1 levels. However, after adjustment for age, the association between plasma levels of insulin-like growth factor binding protein 3 (IGFBP-3) and breast cancer approached statistical significance; OR for highest quintile versus lowest quintile of IGFBP-3 being 2.05 (95% CI, 0.93–4.53). All results were independent of diet and other known risk factors for breast cancer. Conclusion: Circulating insulin levels and possibly IGFBP-3 levels are elevated in women with premenopausal breast cancer. This association may reflect an underlying syndrome of insulin resistance that is independent of obesity.     

Regularity and length of menstrual cycles in women aged 41–46 in relation to breast cancer risk: Results from the DOM-project

Summary The effect of regularity and length of the menstrual cycle on breast cancer risk was studied prospectively in 78 cases and 383 age-matched controls who participated in a breast cancer screening programme, the DOM-project, in Utrecht, the Netherlands. Before entering the screening programme when they were aged 41–46, the women kept a menstrual calendar during at least three consecutive cycles. Cycles were considered to be irregular if any of three cycles was shorter than 21 days or longer than 35 days and/or if variation between cycle lengths was more than five days. Women with irregular cycles had a significantly reduced risk of breast cancer (odds ratio = 0.44; 95% confidence interval 0.22–0.86) after adjustment for age at menarche, age at first birth, parity, Quetelet's index and family history of breast cancer. Among regularly menstruating women, long cycles (28 days or more) were not significantly associated with increased risk of breast cancer (odds ratio 1.17; 95% confidence interval 0.66–2.09).To the extent that irregular menstrual cycles reflect anovulatory cycles, our findings support the hypothesis that the cumulative number of regular ovulatory cycles increases breast cancer risk.