Association Of Pregnancy Research Articles

Abstract P2-05-03: Integrated analysis of mismatch repair, PD-L1, and immune microenvironment status in pregnancy-associated breast cancers

Abstract Introduction: Breast cancer (BC) occurring during gestation or lactation is rare, yet highly challenging under both biological and clinical standpoints. This condition, referred to as pregnancy-associated (PA) BC (PABC), shows enrichment in mismatch repair (MMR) deficiency mutational signature, higher expression of immune-checkpoint genes, and less tumor-infiltrating lymphocytes (TILs) compared to non-PA BCs. Despite these insights, no comprehensive data on MMR protein status, immune checkpoints, and immune microenvironment are currently available for these tumors. The aim of this study was to characterize the MMR status and immunologic milieu of PABC. Methods: Among a multi-Institutional database comprising 142 PABCs, we conducted a comparative analysis of a cohort of PABC (n=29) and a control group of age-matched non-PA BCs (n=74). Distinct areas of each tumor and the corresponding normal breast tissue were incorporated into a tissue microarray (4-6 cores per case, mean 4.5). For all cases, both stromal and intratumoral TILs were quantified according to the International TILs Working Group recommendations. Representative slides were subjected to immunohistochemical (IHC) analysis of the MMR proteins (i.e. MLH1, MSH2, MSH6, and PMS2), programmed death-ligand 1 (PD-L1), CD4, and CD8. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and, when the protein was expressed only in a part of the tumor, MMR-heterogeneous (hMMR). PD-L1 expression was evaluated separately in the tumor cells, stromal TILs, and intratumoral TILs. Finally, the relative proportion of CD4+ and CD8+ cells was assessed in both stromal and intratumoral TILs. Results: The study group included 4 (14%) Luminal A, 10 (35%) Luminal B, 4 (14%) non-luminal HER2+, and 11 (37%) triple-negative (TN) PABCs. Taken together, both the dMMR and hMMR status were more common in PABCs than in non-PA BC (n=3/29, 19% vs. n=6/74, 8% and n=7/29, 24% vs. 14/74, 19%, respectively). Specifically, dMMR was seen in Luminal A (n=2, 50%) and in TN (n=1, 9%) PABCs. Conversely, in non-PA BCs, all Luminal A (n=15, 100%) were pMMR, while 5/45(11%) Luminal B and 1/13 (7%) TNBC were dMMR. Despite no differences were observed in intratumoral TILs, PABCs showed significantly higher levels of stromal TILs (p=0.01). Compared to the control group, PD-L1 expression in PABCs was significantly higher in the tumor cells and in stromal TILs (p<0.01) but not in intratumoral TILs. Hence, 9 (31%) PABCs were PD-L1+, with tumor proportion scores (TPS) ranging from 2 to 10 (mean 5), while only 4 (5%) non-PA BCs were PD-L1+ (TPS 2-20, mean 8)(p=0.01). The expression of PD-L1 in stromal TILs was higher in PABCs (n=9, 31%) than in the controls (n=19, 26%)(p=0.005). In Luminal tumors, both the CD4+ and CD8+ populations were more represented than in non-PA BCs (p=0.01), while in TNBC only the relative proportion of CD4+ cells was significantly higher (p=0.02). Discussion: This study is the first to investigate the immune response alongside the MMR status by IHC in PABCs. Our findings broaden the understanding of the immunobiology underpinning PABC, suggesting that in these tumors i) MMR protein alterations occur at higher frequency than in non-PA BCs; ii) the tumor cells and tumor microenvironment may be capable to suppress the adaptive arm of immune system through the expression of PD-L1; and iii) lymphocytes located at the periphery rather than those inside of the tumor are likely to be implicated in the immune modulation. Conclusion: The MMR system and immune microenvironment may play a consistent role in the natural history of PABCs. An intimate knowledge of the multifaceted interplay between tumor and tumor immune microenvironment is likely to unveil clinically relevant mechanisms that may have a positive net health impact for women with BC during gestation or lactation. Citation Format: Nicola Fusco, Elena Guerini-Rocco, Barbara Buonomo, Roberto Croci, Caterina Fumagalli, Gianluca Lopez, Giorgio A Croci, Letterio Runza, Elham Sajjadi, Concetta Blundo, Luca Despini, Massimo Giroda, Viviana E Galimberti, Paolo Veronesi, Massimo Barberis, Stefano Ferrero, Giovanna Scarfone, Silvano Bosari, Giuseppe Viale, Fedro Peccatori. Integrated analysis of mismatch repair, PD-L1, and immune microenvironment status in pregnancy-associated breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-03.

718: Drug-related maternal deaths in Utah, 2013-2016

The Utah Perinatal Mortality Review is a multi-disciplinary committee that reviews all maternal and infant deaths in Utah. We described causes of maternal deaths in Utah from 2013-16, and evaluated the impact of committee classification of drug-related deaths as pregnancy-related (rather than pregnancy-associated) beginning in 2015. Retrospective review of all Utah maternal deaths from 2013-16. Pregnancy-associated (PA) death defined as death of a woman during pregnancy or within one year of the end of pregnancy, regardless of cause. Pregnancy-related (PR) death defined as death of a woman in the same time period, from a pregnancy complication, a chain of events initiated by pregnancy, or the aggravation of an unrelated condition by the physiologic effects of pregnancy. Accidental drug-related deaths included deaths from prescribed and illicit drugs. Contributing factors, defined by Centers for Disease Control and Prevention, were identified for each death. Beginning in 2015, the Committee classified accidental drug-related deaths as PR given mounting evidence that substance use disorder (SUD) and mental health (MH) conditions may be aggravated during pregnancy and in the post-partum period. To assess the impact of reclassifying accidental drug-related death as PR, we compared the PR mortality ratio in Utah in 2013-2016 using test of trend. In 2015-2016, 40 PA deaths and 26 PR deaths occurred: accidental drug toxicity was the leading cause of both PA (n=10, 25%) and PR (n=10, 38%) death (Figure 1). In 2015-2016, all women with accidental drug-related deaths had MH conditions and 80% of these deaths occurred 43-365 days postpartum. For all PA deaths (n=40), contributing factors included SUD (n=18, 45%), mental health conditions (n=16, 40%) and clinical issues, namely inadequate screening and treatment for SUD and MH conditions (n=15, 38%). In 2013-2014, there were 44 PA deaths. Leading causes were motor vehicle accident (n=10, 20%) followed by accidental drug-related death (n=7, 17.5%) (Figure 1). From 2013-2016, there was no significant increase in PR deaths attributable to reclassification of drug-related deaths as PR (p=0.06) (Figure 2). Accidental drug-related death was the most common identifiable cause of PR death in Utah in 2015-6 following reclassification of drug-related deaths as PR. Effective interventions aimed at identifying and treating pregnant and postpartum women with SUD and MH conditions are imperative.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Prevalence of unintended pregnancy and its associated factors among sexually active never‐married youth in Shanghai

This study was conducted to determine the prevalence and the associated factors for unintended pregnancy among never-married sexually active youth (15-24 years old) in Shanghai. Using a probability sample (n = 765, including 502 males and 263 females) from 2006, we estimated prevalence of unintended pregnancy involvement for females and males by demographic factors and its associations with contextual and behavioural factors, guided by a social-ecological framework. Weighted proportion analyses estimated that 13.8% of females and 17.7% of males had been involved in an unintended pregnancy, and 99.0% and 90.5% of such pregnancies were reported to have ended in abortion by females and males, respectively. Controlling for sexual behaviour factors and residence history, multivariate hazard analyses with Weibull functions found increased hazard among older female youth (19-21 vs. 15-18 years old) but decreased hazard among older male youth (15-18 vs. 19-21/22-24 years old) as compared with the younger groups. Parallel analyses of unintended pregnancy's associations with contextual factors by sex also suggested that female unintended pregnancy involvement was more likely to be associated with family factors (family living arrangements and maternal education), while unintended pregnancy involvement among males was only associated with school factors (school climate and sex education on pregnancy) and perceived neighbourhood contraceptive services access. Sexually active and never-married youth are at considerable risk of unintended pregnancy and abortion in Shanghai. Age- and sex-specific strategies will be needed if China is going to be successful in addressing unintended pregnancy.

Cytotoxic chemotherapy for pregnancy-associated breast cancer: single institution case series

Pregnancy-associated (PA) breast cancer is a rare disease state that poses unique management challenges, specifically controlling the cancer and maximizing the survival of the expectant mother balanced with the health and safety of the developing fetus. As more women delay pregnancy into their 30s and 40s it is expected that this may become a more important clinical problem in the future. Existing data on PA-breast cancer comes from case series using older chemotherapy drugs. A review of practice was carried out to assess current experience with PA-breast cancer, particularly relating to current cytotoxic drugs and targeted agents. The St James's Hospital breast cancer registry, a prospectively maintained database, was used to identify cases of PA-breast cancer over a 6.5-year period and a chart review carried out. Chemotherapy administered during pregnancy, breast cancer specific outcomes, and fetal outcomes were assessed. Five patients were identified with PA-breast cancer; median age 34 years (range 28-35). The median gestation at presentation was 18 weeks (range 14-29). Four women received chemotherapy during pregnancy; three received doxorubicin and cyclophosphamide (AC) and one paclitaxel. These agents were generally well tolerated. At median gestation of 36 weeks (range 35-40 weeks) four elective caesareans and one spontaneous delivery occurred. There were no fetal abnormalities. Common cytotoxics can safely be delivered in pregnancy. Further research on newer therapies such as trastuzumab is needed.

Prenatal Exposure to Wartime Famine and Development of Antisocial Personality Disorder in Early Adulthood

ContextSeveral observational epidemiological studies report an association of pregnancy and obstetric complications with development of antisocial personality disorder (ASPD) in offspring. However, the precise nature and timing of the hypothesized biological insults are not known.ObjectiveTo test whether severe maternal nutritional deficiency early in gestation is associated with risk for ASPD in offspring.Design and SettingRetrospective cohort study. From October 1944 to May 1945, the German army blockaded food supplies to the Netherlands, subjecting the western Netherlands first to moderate (official food rations, 4200-6300 kJ/d) then to severe (<4200 kJ/d) nutritional deficiency. The north and south were subjected to moderate nutritional deficiency only.ParticipantsDutch men born in large urban areas in 1944-1946 who were given psychiatric examinations for military induction at age 18 years (N=100,543) were classified by the degree and timing of their prenatal exposure to nutritional deficiency based on their birthdate and birthplace.Main Outcome MeasureDiagnosis of ASPD by psychiatric interview at time of medical examination for military induction, using the International Classification of Diseases, Sixth Revision (ICD-6).ResultsMen exposed prenatally to severe maternal nutritional deficiency during the first and/or second trimesters of pregnancy exhibited increased risk for ASPD (adjusted odds ratio [OR], 2.5; 95% confidence interval [CI], 1.5-4.2). Third-trimester exposure to severe nutritional deficiency and prenatal exposure to moderate nutritional deficiency were not associated with risk for ASPD.ConclusionsOur data suggest that severe nutritional insults to the developing brain in utero may be capable of increasing the risk for antisocial behaviors in offspring. The possible implications of these findings for both developed countries and developing countries, where severe nutritional deficiency is widespread and often exacerbated by war, natural disaster, and forced migration, warrant study.

Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger.

To evaluate the purported decreased survival of pregnancy-associated (PA) breast cancer, a previously described homogeneous cohort of women of childbearing age with primary operable cancer was studied. The current analysis was designed to (a) identify those patients among the cohort known to have PA cancer and (b) compare clinical factors, pathologic characteristics, stage at diagnosis, and survival statistics for PA and non-PA cancer subgroups. All patients < or =30 years of age who underwent definitive operation between 1950 and 1989 at the Memorial Sloan-Kettering Cancer Center (MSKCC) for primary operable (stages 0-IIIA) breast adenocarcinoma were analyzed. Twenty-two of the 227 young women with primary operable breast cancer had PA cancer. Disease-related survival was decreased (p = 0.004) in these 22 women compared with the remaining 205 patients with non-PA cancer. PA cancer patients were found to have larger tumors (p < 0.005), and a greater proportion had advanced staged (IIB or IIIA) cancers (p < 0.02). Among patients diagnosed with early invasive cancers (stages I or IIA), no difference (p = NS) in survival was observed comparing PA and non-PA subgroups (73% vs. 74% 10-year survival). Patients with stage IIIA cancer had shorter disease-free and overall survival when associated with pregnancy (0% vs. 35% 10-year survival). Women 30 years of age or younger with PA breast cancer have decreased survival compared with patients with non-PA cancer from the same cohort. Women with PA cancer have larger, more advanced cancers at the time of definitive surgery. Women with early staged PA cancers appear to have survival similar to that for women with early staged non-PA cancer.

Pregnancy-associated breast cancer

The incidence of pregnancy-associated (PA) breast cancer is rising, as childbirth is being delayed to the women's 30s and early 40s, when breast cancer is more frequent. Most reports consider "PA breast cancer" as that being diagnosed during pregnancy, or within one year after. The delay of diagnosis often seen in PA breast cancer may be due to physician oversight or reluctance to perform a biopsy during pregnancy. Two-stage procedures are favored in this setting, with biopsy under local anesthesia, then extent-of-disease work-up and definitive treatment, usually mastectomy. The use of scans for staging, and irradiation for treatment, is avoided, where possible, due to fetal risk. Likewise, chemotherapy is carefully gauged to avoid fetal damage. With these precautions, the prognosis for women with PA breast cancer, stage for stage, is similar to that of women of the same age treated at the same time period at MSKCC.

Prognosis of Pregnancy-Associated Breast Cancer

The survival of patients with pregnancy-associated (PA) breast cancer is difficult to predict for two reasons: The combination is very rare, and the natural history of breast cancer that is not associated with pregnancy is intricate and varies among individuals. Valid data collection and analysis is problematic given that studies gather patients over many years. The charts of 56 women with Stages I, II, and III breast cancer, who were pregnant or within 1 year postpartum at the time of breast cancer diagnosis between 1960 and 1980, were analyzed. Patients with PA breast cancer were compared to nonpregnant women of comparable ages, who were treated at the same hospital, by the same physicians, and during the same period. Four patients were lost before 5-year follow-up, and one patient before 10-year follow-up. These five patients had distant metastases at the time they were lost to follow-up, and are considered to have died within that time. Across stages, patients with PA breast cancer have survival not significantly different from those patients with non-pregnancy-associated (non-PA) breast cancer.

Prognosis of pregnancy-associated breast cancer

The survival of patients with pregnancy-associated (PA) breast cancer is difficult to predict for two reasons: The combination is very rare, and the natural history of breast cancer that is not associated with pregnancy is intricate and varies among individuals. Valid data collection and analysis is problematic given that studies gather patients over many years. The charts of 56 women with Stages I, II, and III breast cancer, who were pregnant or within 1 year postpartum at the time of breast cancer diagnosis between 1960 and 1980, were analyzed. Patients with PA breast cancer were compared to nonpregnant women of comparable ages, who were treated at the same hospital, by the same physicians, and during the same period. Four patients were lost before 5-year follow-up, and one patient before 10-year follow-up. These five patients had distant metastases at the time they were lost to follow-up, and are considered to have died within that time. Across stages, patients with PA breast cancer have survival not significantly different from those patients with non-pregnancy-associated (non-PA) breast cancer.