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Safety of pregnancy in women with history of estrogen receptor (ER)-positive breast cancer remains controversial. In this multicenter case-control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaranteed time bias. Survival estimates were calculated using the Kaplan-Meier analysis; groups were compared with the log-rank test. All reported P values were two-sided. At a median follow-up of 7.2 years after pregnancy, no difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.70 to 1.26, P = .68) or ER-negative (HR = 0.75, 95% CI = 0.53 to 1.06, P = .10) disease. No overall survival (OS) difference was observed in ER-positive patients (HR = 0.84, 95% CI = 0.60 to 1.18, P = .32); ER-negative patients in the pregnant cohort had better OS (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). Abortion, time to pregnancy, breastfeeding, and type of adjuvant therapy had no impact on patients' outcomes. This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.

Background: The increase in breast cancer risk during pregnancy and postpartum is well known; however, the molecular phenotype of breast cancers occurring shortly after pregnancy has not been well studied. Given this, we investigated whether nulliparity and the time interval since pregnancy among parous women affects the breast cancer phenotype in young women., Materials and Methods: We examined molecular phenotype in relation to time since pregnancy in a prospective cohort of 707 young women (aged ≤40 years) with breast cancer. Parity was ascertained from study questionnaires. Using tumor histologic grade on central review and biomarker expression, cancers were categorized as luminal A- or B-like, HER2 enriched, and triple negative., Results: Overall, 32% were luminal A-like, 41% were luminal B-like, 9% were HER2 enriched, and 18% were triple negative. Although, numerically, patients diagnosed >5 years after pregnancy had more luminal A-like subtypes than women with shorter intervals since pregnancy, there was no evidence of a relationship between these intervals and molecular subtypes once family history of breast cancer and age at diagnosis were considered., Conclusion: Distribution of breast cancer molecular phenotype did not differ significantly among young women by parity or time interval since parturition when important predictors of tumor phenotype such as age and family history were considered., Implications for Practice: Distribution of breast cancer molecular phenotype did not differ among parous young women by time interval since pregnancy. The implication of these findings for clinical practice suggests that pregnancy-associated breast cancers may be seen up to 5 years beyond parturition., (©AlphaMed Press.)

Breast cancer rarely occurs in women below the age of 35 years. Data from various sources indicate that diagnosis at such an age is associated with a dire prognosis mainly because of a more aggressive presentation. Although the effect of chemotherapy for premenopausal patients is substantial, recent evidence on 2233 patients suggested that very young women with endocrine-responsive tumors had a statistically significantly higher risk of relapse than older premenopausal patients with such tumors. In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine nonresponsive. Information from studies on 7631 patients who were treated with chemotherapy alone in trials of three major U.S. cooperative groups showed a similar interaction between the effect of age and steroid hormone receptor status of the primary tumor. Better treatments for very young patients are required and may involve ovarian function suppression in addition to other endocrine agents in patients with endocrine responsive tumors and a more precise investigation of chemotherapy and its timing, duration, and intensity in those with endocrine nonresponsive tumors. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues, which further complicate the phase of treatment decision making. The development of more effective therapies for younger patients requires tailored treatment investigations and cannot rely on information predominantly contributed from older premenopausal women.

We investigated the effects of 8 days of LH withdrawal on rat Leydig cell peroxisomal volume, total and intraperoxisomal catalase and sterol carrier protein-2 (SCP2) contents, and LH-stimulated testosterone secretion in vitro. Three groups of adult male Sprague-Dawley rats, i.e. control, TE-implanted (testosterone-17 beta-estradiol-filled Silastic implants to suppress LH), and TELH-implanted (TE-implanted and LH replacement via Alzet mini osmotic pumps), were used. After 8 days, Leydig cell organelle volumes (stereology), intraperoxisomal catalase and SCP2 contents (immunocytochemistry), LH-stimulated testosterone secretion by isolated Leydig cells in vitro (determined by RIA), and total catalase and SCP2 contents in equal numbers of Leydig cells (immunoblot analyses) were determined. Results showed that the TELH-implanted rats were identical to controls in every parameter tested. Testis volume and Leydig cell number per testis in control and TE-implanted rats were not significantly different; however, reductions (P < 0.05) were observed in the average volume of a Leydig cell (one third of controls) and the volume of Leydig cells per testis. All Leydig cell organelle volumes tested were significantly lower in TE-implanted rats than in the controls; however, the volumes of smooth endoplasmic reticulum (SER) and peroxisomes were the most reduced (lowered to one sixth of control values). LH-stimulated testosterone secretion per Leydig cell in vitro correlated well with these changes in the volumes of Leydig cell SER and peroxisomes. Intraperoxisomal catalase in Leydig cells was unchanged in TE-implanted rats, although immunoblotting demonstrated a loss of total catalase content (which reflected the reduction in the volume of peroxisomes). SCP2 in Leydig cells of TE-implanted rats was undetectable with immunoblot analysis (explained by the reductions in Leydig cell peroxisome volume and intraperoxisomal SCP2). These results demonstrate that the organelles SER and peroxisomes and the protein SCP2 in Leydig cells are more LH dependent than the other organelles (e.g. mitochondria, lysosomes) and protein catalase, respectively. Moreover, the findings of this study are consistent with the hypothesis that Leydig cell peroxisomes play a significant role in testosterone production.

The aim of the present study was to investigate the effects of a single injection of LH on rat Leydig cell peroxisome volume and peroxisomal sterol carrier protein-2 (SCP2) content. Sexually mature Sprague-Dawley rats (n = 5) were injected sc with 500 micrograms LH and euthanized, and trunk blood was collected at 0, 0.5, 1, 2, and 3 h. Additionally, LH-treated rats were whole body perfused-fixed, and their testes were processed for qualitative and quantitative histochemical and immunocytochemical studies at 0, 0.5, 1, and 2 h. Peroxisomes were identified by cytochemical staining for catalase activity with the alkaline 3,3'-diaminobenzidine tetrahydrochloride method. Catalase and SCP2 were immunolocalized in Leydig cell organelles via 10-nm AuroProbe EM protein-A gold particles. Peak plasma testosterone concentrations were observed 1 and 2 h after the single sc LH injection. The average volume of a Leydig cell was unchanged by the LH treatment at all time points tested. Similarly, the absolute volumes of smooth endoplasmic reticulum and mitochondria per Leydig cell were unchanged at all time points tested. By contrast, the absolute volume of peroxisomes per Leydig cell increased 3-fold 0.5 h after LH injection (P less than 0.01) and then returned to control values by 2 h. The absolute volume of negative bodies (single membrane-bound cytoplasmic organelles lacking catalase) per Leydig cell was elevated above the control value 0.5 and 1 h after LH injection. Western blot analysis demonstrated a single protein at 14 and 60 kDa with anti-SCP2 and anticatalase, respectively, for both homogenates obtained from liver and purified Leydig cells. Quantitative immunocytochemical studies demonstrated that the gold particle density representing SCP2 over peroxisomes increased 5-fold 0.5 h after the LH injection (P less than 0.01) and then returned to control values by 2 h. In contrast, the gold particle density representing catalase over peroxisomes was not different in control and LH-injected groups. We conclude that a single sc injection of LH causes a rapid, specific, and transient increase in both the volume of peroxisomes and the peroxisomal content of SCP2 in Leydig cells.

The neonatal period is a time of transition between pituitary-independent fetal growth and the pituitary-dependent growth seen in older mammals. To evaluate pituitary-dependent neonatal growth, Wistar rats were hypophysectomized (Hx) on postnatal day 6. Nineteen days post-Hx, body weight and tail length were inhibited 48% and 34%, respectively, compared with sham-Hx controls. Organ weights determined on days 10, 15, 20, 25, and 30 revealed three patterns of pituitary-dependence: 1) pituitary-independent growth in the brain and lung; 2) moderate pituitary-dependent growth in the heart, liver, kidney, and intestine; and 3) marked pituitary-dependent growth in the adrenals, spleen, and testes. Both serum insulin-like growth factor (IGF)-I and -II levels fell significantly in Hx pups by 54 h after Hx (P = 0.0005), and Northern analysis on day 15 showed a significant decrease in liver messenger RNA (mRNA) for IGF-II. Analysis of the major IGF binding proteins (BPs) was performed by Western ligand blots. Hx performed on day 6 resulted in a linear decrease in the amount of the 22k BP from day 10 to day 30. In contrast, the major neonatal BP (IGFBP-2, a 29.5k molecule) showed a biphasic response to neonatal Hx. On postnatal day 10, 4 days after Hx, a significant decrease in IGFBP-2 occurred, which persisted through day 15; by postnatal day 20 and continuing through postnatal day 30, the amount of IGFBP-2 in the serum dramatically increased. The 40 to 50k fraction of IGFBP-3 first appeared in significant quantities by postnatal day 20, and after Hx dropped to 10% of sham-control values. Similarly, Northern analysis on day 15 demonstrated a significant decrease in liver, but not brain, mRNA for IGFBP-2 after Hx, whereas on postnatal day 25, liver mRNA for IGFBP-2 was increased in Hx pups compared with sham controls. We conclude that the pituitary gland exerts significant but selective effects on neonatal growth, with the notable exception of brain growth. Serum levels of both IGF-I and IGF-II, as well as their BPs, are pituitary dependent in the neonatal period. Pituitary-dependent neonatal growth thus appears to be mediated by IGF and modulated by IGF-binding proteins. On the other hand, that portion of the persistent growth in the neonatal Hx rat that is independent of the pituitary-IGF axis may be a good model for investigation of fetal growth.