Racial and Ethnic Disparities in Rates of Invasive Second Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawai'i.

Importance: Women with ductal carcinoma in situ (DCIS) may develop a subsequent invasive second breast cancer (SBC). Understanding the association of racial and ethnic factors with the development of invasive SBC may help reduce overtreatment and undertreatment of women from minority groups. Objective: To evaluate risk factors associated with developing invasive ipsilateral SBC (iiSBC) and invasive contralateral SBC (icSBC) among women with an initial diagnosis of DCIS who are from racial and ethnic minority populations. Design, Setting, and Participants: This retrospective cohort study used deidentified data from the Hawai'i Tumor Registry of 6221 female Hawai'i residents aged 20 years or older who received a diagnosis of DCIS between January 1, 1973, and December 31, 2017. The 5 most populous ethnic groups were compared (Chinese, Filipino, Japanese, Native Hawaiian, and White). Data analysis was performed from 2020 to 2021. Exposures: Patient demographic and clinical characteristics and the first course of treatment. Main Outcome and Measures: The a priori study outcome was the development of invasive SBC. Logistic regression was used to identify factors associated with invasive SBC. Factors that were significant on unadjusted analyses were included in the adjusted models (ie, age, race and ethnicity, diagnosis year, DCIS histologic characteristics, laterality, hormone status, and treatment). Results: The racial and ethnic distribution of patients with DCIS across the state's most populous groups were 2270 Japanese women (37%), 1411 White women (23%), 840 Filipino women (14%), 821 Native Hawaiian women (13%), and 491 Chinese women (8%). Women of other minority race and ethnicity collectively comprised 6% of cases (n = 388). A total of 6221 women (age range, 20 to ≥80 years) were included in the study; 4817 (77%) were 50 years of age or older, 4452 (72%) received a diagnosis between 2000 and 2017, 2581 (42%) had well or moderately differentiated histologic characteristics, 2383 (38%) had noninfiltrating intraductal DCIS, and 2011 (32%) were treated with mastectomy only. Of these 6221 women, 444 (7%) developed invasive SBC; 190 developed iiSBC (median time to SBC diagnosis, 7.8 years [range, 0.5-30 years]) and 254 developed icSBC (median time to SBC diagnosis, 5.9 years [range, 0.5-28.8 years]). On adjusted analysis, women who developed iiSBC were more likely to be younger than 50 years (adjusted odds ratio [aOR], 1.49; 95% CI, 1.08-2.06), Native Hawaiian (aOR, 3.28; 95% CI, 2.01-5.35), Filipino (aOR, 1.94; 95% CI, 1.11-3.42), Japanese (aOR, 1.58; 95% CI, 1.01-2.48), and untreated (aOR, 2.29; 95% CI, 1.09-4.80). Compared with breast-conserving surgery (BCS) alone, there was a decreased likelihood of iiSBC among women receiving BCS and radiotherapy (aOR, 0.45; 95% CI, 0.27-0.75), BCS and systemic treatment with or without radiotherapy (aOR, 0.40; 95% CI, 0.23-0.69), mastectomy only (aOR, 0.23; 95% CI, 0.13-0.39), and mastectomy and systemic treatment (aOR, 0.57; 95% CI, 0.33-0.96). Women who developed an icSBC were more likely to be Native Hawaiian (aOR, 1.69; 95% CI, 1.10-2.61) or Filipino (aOR, 1.70; 95% CI, 1.10-2.63). Risk of both iiSBC and icSBC decreased in the later years of diagnosis (2000-2017) compared with the earlier years (1973-1999). Conclusions and Relevance: This study suggests that Native Hawaiian and Filipino women who initially received a diagnosis of DCIS were more likely to subsequently develop both iiSBC and icSBC. Japanese women and younger women were more likely to develop iiSBC. Subpopulation disaggregation may help guide clinical treatment and screening decisions for at-risk subpopulations.

Prognostic value of PSMA, c-MET and E-cadherin in salivary duct carcinoma.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.

Ultrasound Imaging Characteristics of Breast Lesions Diagnosed During Pregnancy and Lactation.

Background and Objectives: The breast undergoes extensive physiologic changes during pregnancy/lactation. We aimed to review the ultrasound (US) imaging characteristics of breast lesions during pregnancy/lactation and to demonstrate ultrasonography as an excellent imaging modality in this patient population. Materials and Methods: We performed a retrospective study involving 195 patients with 206 pathologically confirmed breast lesions during pregnancy/lactation over the period of January 2010 to December 2018; 51 were diagnosed with breast cancer, including 50 invasive ductal carcinomas and 1 low malignant potential phyllodes tumor, whereas 144 were diagnosed with 155 benign lesions, including 103 mastitis/abscesses, 45 fibroadenomas, 2 intraductal papillomas, 2 sclerosing lesions, and 3 benign phyllodes tumors. The patients' age, lesion diameter, and US characteristics were analyzed. Results: The breast lesions of patients during pregnancy/lactation were compared with those during nonpregnancy/lactation. Patients with breast cancer or fibroadenomas during pregnancy/lactation were younger than those during nonpregnancy/lactation. The average lesion diameter was significantly higher among pregnant/lactating patients compared with controls of childbearing age for fibroadenomas, but not for malignant lesions. The fibroadenomas and mastitis/abscesses during pregnancy/lactation usually have higher BI-RADS categories than those during nonpregnancy/lactation. Conclusions: The imaging features of breast cancer during pregnancy/lactation did not differ much from those of nonpregnancy/lactation; however, some benign lesions had suspicious sonographic features, and US-guided core biopsies were necessary for differentiating benign from malignant lesions.

The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation.

Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.

Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity.

Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT) has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences.

Adenocarcinoma prostático de grandes ductos / Prostatic adenocarcinoma of large ducts

INTRODUCCIÓN: Más del 90% del cáncer de próstata (CP) es de origen acinar. Una de las variantes es el carcinoma que se origina de los grandes ductos parauretrales. CASO CLÍNICO: Se presenta el caso de un varón de 62 años visitado por hematuria microscópica. La evaluación inicial destaca tacto rectal negativo, cistoscopia y citología urinaria ambos normales. PSA: 1.87ng / l. Después de 3 años de seguimiento nueva hematuria. Cistoscopia: tumoración en cuello vesical. Citología de orina: negativa. Tacto rectal: nódulo de 3mm. Se realiza biopsia de próstata: adenocarcinoma de próstata Gleason 4 +4 con extensa afectación tipo PIN de alto grado. Se realizó prostatectomía radical: Diagnóstico final: carcinoma prostático de grandes ductos, Gleason 4 +5, pT2a. DISCUSIÓN: El adenocarcinoma ductal de la próstata está compuesto por estructuras papilares o cribosas. Con menor frecuencia existe patrón con células columnares y aspecto pseudoestratificado. Sólo el 0.2-0.8 % de CP corresponden a formas puras de carcinoma de grandes ductos. Varios estudios consideran que la morfología ductal connota un curso más agresivo. El adenocarcinoma ductal de próstata debe gradarse con un score de Gleason 4+4 (AU)

INTRODUCTION: Over 90% of prostate cancer (PC) is of acinar origin. One variant is carcinoma that originates from the paraurethral ducts large. CASE REPORT: We report the case of a man of 62 years visited by microscopic hematuria. The initial assessment highlights negative digital rectal examination, cystoscopy and urine cytology both normal. PSA: 1.87ng /ml. After 3 years of follow up he show new hematuria. Cystoscopy: Tumor in the bladder neck. Urine cytology: negative. Digital rectal nodule of 3 mm. Prostate biopsy: prostate adenocarcinoma Gleason 4 +4 with extensive high grade PIN. It was performed radical prostatectomy. Final diagnosis: prostate carcinoma of large ducts, Gleason 4 +5, pT2a. DISCUSSION: Ductal adenocarcinoma of the prostate is composed of papillary structures or sieve. Less frequently there is pattern and appearance pseudostratified columnar cells. Only 0.2-0.8% of CP correspond to pure forms of carcinoma of large ducts. Several studies consider ductal morphology connotes a more aggressive course. Ductal adenocarcinoma of the prostate Should be classified as Gleason score 4 +4 (AU)

Histopathological evidence for an association of inflammation with ductal pin-like lesions but not with ductal adenocarcinoma in the prostate of the noble rat.

BACKGROUND: Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis. METHODS: Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks. Hormone dependency of the lesions was studied in a subset of animals by removing hormone implants for 3 weeks after 15 weeks treatment time. RESULTS: After treatment for 13 weeks, acute and chronic inflammation was found in the dorsolateral prostate lobes and both inflammation and PIN-like lesions were present in the periurethal area of the prostate in all animals (n = 8). Following hormone exposure for 18 and 26 weeks, inflammation in the prostate remained, and adenocarcinomas in the periurethal prostate area with no adjacent inflammation were observed in all 18 animals studied. When both hormone implants were removed after 15 weeks, PIN-like lesions progressed further to adenocarcinoma only in two of seven animals. When only the estradiol implants were removed, three of five animals developed adenocarcinomas. CONCLUSIONS: Even though adenocarcinomas were not morphologically associated with inflammation, PIN-like lesions preceding adenocarcinoma were found in close association with inflammation, pointing towards a possible initiator role of inflammation in the early steps of prostatic carcinogenesis. Further, these results indicate that both androgens and estrogens together play a significant role in the induction of inflammation and prostatic cancer in this model.

Relationship between age maximum height is attained, age at menarche, and age at first full-term birth and breast cancer risk.

Several pubertal and reproductive events are well established risk factors for breast cancer. Age maximum height attained is an understudied potential breast cancer risk factor that may affect risk through mechanisms different from those of other pubertal and reproductive events. We assessed the relationships between different pubertal/reproductive events and risk of different types of breast cancer in a prospective cohort of 27,536 women. Women were recruited between 2000 and 2002 and completed a mailed questionnaire. As of 2005, 585 women were diagnosed with breast cancer. Using a Cox proportional hazards model, women who reached their maximum height at or=17 years of age (P(trend) = 0.04). This association was primarily limited to more aggressive tumors, specifically those that were estrogen receptor-negative (hazard ratio, 1.9; 95% CI, 1.0-3.9) and diagnosed at a regional or distant stage (hazard ratio, 1.8; 95% CI, 1.0-3.1). There was no difference in the relation of age at menarche with breast cancer by tumor stage, whereas late age at first full-term pregnancy primarily increased risks of less-aggressive disease, including lobular, estrogen receptor-positive, and localized stage tumors. Age at maximum height seems to be an independent risk factor for breast cancer that is more strongly associated with relatively aggressive tumors that have a poorer prognosis compared with the types of tumors that are associated with ages at menarche and first full-term birth.

Activation of NF-kappaB in association with prostate carcinogenesis in noble rats.

There is an increasing interest in the role of chronic nonbacterial prostatitis in the development of prostate cancer. The aim of the study was to explore the role of NF-kappaB in the prostate of Noble rats treated with testosterone (T) and 17beta-estradiol (E(2)), a widely used model for prostate carcinogenesis. NF-kappaB-positive epithelial cells appeared in both inflamed and noninflamed glands and ducts at 13 weeks after hormone implantation in hypoandrogenemic, hyperestrogenemic rats. Both nuclear and cytoplasmic staining were observed. When daily dose of T was increased to give serum concentration above the level of control animals, dysplastic lesions and ductal carcinomas with NF-kappaB-positive cells were induced at 13 weeks and 26 weeks. The number of acini with NF-kappaB-positive cells decreased and no nuclear staining was observed. Surprisingly, no inflammation was seen in the periurethral region where ductal carcinomas developed. In conclusion, no unequivocal evidence was obtained to support the idea that NF-kappaB would be activated in association with inflammation in the development of ductal carcinomas. The hormonal control of NF-kappaB in the prostate warrants further studies.

An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk.

Results from the Women's Health Initiative (WHI) trial support findings from observational studies that oestrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. We conducted a meta-analysis using EPT-specific results from the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) pooled analysis and studies published since that report to obtain an overview of EPT use and breast cancer risk. We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use. We estimate that overall, EPT results in a 7.6% increase in breast cancer risk per year of use. The risk was statistically significantly lower in US studies than in European studies - 5.2 vs 7.9%. There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT. We observed no overall difference in risk for lobular vs ductal carcinoma but did observe a slightly higher risk for current vs past EPT use.

Intraductal papillary mucinous adenoma that arises from pancreatic heterotopia within a meckel diverticulum.

Neoplasia is an unusual complication of Meckel diverticulum. Most tumors of Meckel diverticulum are neuroendocrine or mesenchymal in origin. Adenocarcinomas represent a minority of the tumors that arise in Meckel diverticulum and are generally thought to develop from either endogenous small intestinal epithelium or heterotopic gastric epithelium. Despite the presence of ectopic pancreas in a small fraction of Meckel diverticula, convincing evidence of tumors that arise from heterotopic pancreatic exocrine tissue has not been described in this setting. Intraductal papillary mucinous neoplasms are relatively uncommon tumors of pancreatic ductal epithelial cells that line the main pancreatic duct or its major side branches. We present an unusual case of an intraductal papillary mucinous neoplasm that arose in a heterotopic pancreas within a Meckel diverticulum.

Comparison of age-specific incidence rate patterns for different histopathologic types of breast carcinoma.

OBJECTIVE: The age-specific incidence rate curve for breast carcinoma overall increases rapidly until age 50 years, and then continues to increase at a slower rate for older women. In this analysis, our objective was to compare age-specific incidence rate patterns for different morphologic types of breast carcinoma. MATERIALS AND METHODS: We analyzed age-specific incidence rate curves by histopathologic subclassification using records from 11 standard National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries, diagnosed during the years 1992 to 1999. Data were examined by age <50 and > or /=50 years to simulate menopause. RESULTS: Age-specific incidence rate curves showed three dominant patterns: (1) Rates for infiltrating duct carcinoma of no special type (duct NST), tubular, and lobular carcinomas increased rapidly until age 50 years then rose more slowly. (2) Rates for medullary and inflammatory breast carcinomas increased rapidly until age 50 years then failed to increase. (3) Rates for papillary and mucinous carcinomas increased steadily at all ages. Rate patterns varied by estrogen receptor expression but were unaffected by SEER registry, race, nodal status, or grade. CONCLUSION: Age-specific incidence rates for breast carcinomas differed by histopathologic type. Rates that failed to increase after 50 years suggested that menopause had greater impact on medullary and inflammatory carcinomas than on duct NST, tubular, and lobular carcinomas. Menopause did not seem to have any effect on papillary or mucinous carcinomas as evidenced by steadily rising rates at all ages. Future etiologic and/or prevention studies should consider the impact of age-specific risk factors and/or exposures on different histopathologic types of breast carcinomas.

Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study.

BACKGROUND: The goal of the current study was to investigate the relation between hormone replacement therapy (HRT) and breast carcinoma in a prospective study cohort. Particular attention was paid to the type of HRT used and to the association of HRT type with estrogen receptor status and tumor histology. METHODS: Between 1993 and 1997, a total of 29,875 women were enrolled in the Danish Cancer Society's prospective "Diet, Cancer and Health" study. Among 23,618 women who were assumed to be postmenopausal and for whom information on HRT use was available, we identified 423 cases of breast carcinoma over a median follow-up period of 4.8 years. Statistical analyses were based on the Cox proportional hazards model, with age serving as the time parameter. RESULTS: The breast carcinoma incidence rate ratio (IRR) was 2.22 (95% confidence interval [CI], 1.80-2.75) for users of HRT at baseline compared with women who never received HRT. Among HRT users (relative to nonusers), the IRR for estrogen receptor-positive tumors (2.38; 95% CI, 1.84-3.06) was greater than the IRR for estrogen receptor-negative tumors (1.56; 95% CI, 1.00-2.43). HRT use at baseline also was analyzed in relation to the incidence of lobular carcinoma and the incidence of ductal carcinoma; the adjusted IRR associated with HRT use was 3.53 (95% CI, 1.94-6.41) for lobular carcinoma and 2.10 (95% CI, 1.64-2.70) for ductal carcinoma. The likelihood of developing estrogen receptor-positive breast carcinoma was found to depend significantly on the type of HRT regimen used (P = 0.03), with women receiving continuous therapy having the greatest probability of developing estrogen receptor-positive disease. CONCLUSIONS: An increased breast carcinoma IRR was found to be associated with current HRT use. In addition, relative to other types of HRT regimens, continuous estrogen + progestin regimens were found to be associated with an increased risk of breast carcinoma, and particularly estrogen receptor-positive breast carcinoma.

Oral contraceptive use and risk of breast cancer by histologic type.

We examined the association between oral contraceptive use and risk of specific breast cancer histopathologies in a large, multi-center, population-based, case-control study. Women younger than age 75 with a new diagnosis of invasive breast cancer were identified from 4 statewide tumor registries. We compared women with lobular (n = 493) and ductal carcinoma (n = 5,510) to randomly selected controls (n = 9,311). Odds ratios (OR) and 95% confidence intervals (CI) for each histologic type were estimated using polytomous logistic regression, adjusted for other breast cancer risk factors. Current oral contraceptive use was associated with increased risk of lobular carcinoma (OR = 2.6, 95%CI = 1.0-7.1) and there was a significant trend (p = 0.017) of increased risk with more recent use. Oral contraceptive use was not clearly associated with ductal carcinoma (OR = 1.2, 95%CI = 0.8-1.9). These results suggest that the association between oral contraceptive use and risk of breast cancer may vary by histologic type.

Induced abortion, miscarriage, and breast cancer risk of young women.

Early studies of breast cancer raised substantial concern regarding risk associated with induced abortion and miscarriage. Literature reviews suggest that study findings depend heavily on the comparison group and that the use of parous women as a reference group for nulliparous women may artificially inflate risk. To examine the individual effects of induced abortion and miscarriage on breast cancer risk of parous and nulliparous women, 744 patients < or =40 years of age and diagnosed from 1983-1988 were matched by parity, age, and race with controls living in the same neighborhood in Los Angeles County. In-person interviews were conducted to obtain a detailed reproductive history. Risk estimates were obtained by conditional logistic regression using nulligravid women as the reference group for nulliparous women with a history of incomplete pregnancy and parous women with no incomplete pregnancies as the reference group for parous women with a history of incomplete pregnancy. Breast cancer risk of parous women was unrelated to a history of miscarriage or induced abortion. Breast cancer risk was reduced among nulliparous women with a history of induced abortion relative to nulligravid women, although the risk estimate was imprecise. Risk declined as the number of induced abortions increased (P = 0.04). Our results do not support the hypothesis that induced abortion or miscarriage increase the breast cancer risk of young women.