Weight before and after a diagnosis of breast cancer or ductal carcinoma in situ: a national Australian survey.

BACKGROUND: Overweight/obesity are strongly implicated in breast cancer development, and weight gain post-diagnosis is associated with greater morbidity and all-cause mortality. The aim of this study was to describe the prevalence of overweight/obesity and the pattern of weight gain after diagnosis of breast cancer amongst Australian women. METHODS: We collected sociodemographic, medical, weight and lifestyle data using an anonymous, self-administered online cross-sectional survey between November 2017 and January 2018 from women with breast cancer living in Australia. The sample consisted mainly of members of the Breast Cancer Network Australia Review and Survey Group. RESULTS: From 309 responses we obtained complete pre/post diagnosis weight data in 277 women, and calculated pre/post Body Mass Index (BMI) for 270 women. The proportion of women with overweight/obesity rose from 48.5% at diagnosis to 67.4% at time of survey. Most women were Caucasian with stage I-III breast cancer (n = 254) or ductal carcinoma in situ (DCIS) (n = 33) and mean age was 59.1 years. The majority of women (63.7%) reported they had gained weight after diagnosis with an average increase of 9.07 kg in this group. Of the women who provided complete weight data, half gained 5 kg or more, 17.0% gained > 20 kg, and 60.7% experienced an increase in BMI of >1 kg/m2. Over half of the women rated their concern about weight as high. Of those women who gained weight, more than half reported that this occurred during the first year after diagnosis. Two-thirds (69.1%) of women aged 35-74 years gained, on average, 0.48 kg more weight per year than age-matched controls. CONCLUSIONS: Although the findings from this survey should be interpreted cautiously due to a limited response rate and self-report nature, they suggest that women in Australia gain a considerable amount of weight after a diagnosis of breast cancer/DCIS (in excess of age-matched data for weight gain) and report high levels of concern about their weight. Because weight gain after breast cancer may lead to poorer outcomes, efforts to prevent and manage weight gain must be prioritized and accelerated particularly in the first year after diagnosis.

Quantification of EGFR family in canine mammary ductal carcinomas in situ: implications on the histological graduation.

The epithelial growth factor receptors are transmembrane proteins with an important role in the neoplastic progression of tumors, and in this context, DCIS is an important phase in the progression of canine mammary tumors. Studies on the molecular profile and its relationship to a progression of canine mammary tumors are important to improve the treatment of patients and for a better understanding of canine mammary carcinogenesis. The aim of this study was to determine, by immunohistochemistry, the relation between the expression of EGFR, ErbB-2, ErbB-3, and ErbB-4 in 52 canine mammary gland DCIS with high and low histological grade. A positive correlation between histological grade and expression of membrane ErbB-2 and cytoplasmic ErbB-4 was observed. Increased ErbB-4 membrane expression was correlated with increased ErbB-3 expression in low and high-grade DCIS. Our data suggest that increased expression of ErbB-2 and ErbB-4 may be related to more aggressive DCIS and probabily involved with canine mammary neoplastic progression.

Intra-operative spectroscopic assessment of surgical margins during breast conserving surgery.

BACKGROUND: In over 20% of breast conserving operations, postoperative pathological assessment of the excised tissue reveals positive margins, requiring additional surgery. Current techniques for intra-operative assessment of tumor margins are insufficient in accuracy or resolution to reliably detect small tumors. There is a distinct need for a fast technique to accurately identify tumors smaller than 1 mm2 in large tissue surfaces within 30 min. METHODS: Multi-modal spectral histopathology (MSH), a multimodal imaging technique combining tissue auto-fluorescence and Raman spectroscopy was used to detect microscopic residual tumor at the surface of the excised breast tissue. New algorithms were developed to optimally utilize auto-fluorescence images to guide Raman measurements and achieve the required detection accuracy over large tissue surfaces (up to 4 × 6.5 cm2). Algorithms were trained on 91 breast tissue samples from 65 patients. RESULTS: Independent tests on 121 samples from 107 patients - including 51 fresh, whole excision specimens - detected breast carcinoma on the tissue surface with 95% sensitivity and 82% specificity. One surface of each uncut excision specimen was measured in 12-24 min. The combination of high spatial-resolution auto-fluorescence with specific diagnosis by Raman spectroscopy allows reliable detection even for invasive carcinoma or ductal carcinoma in situ smaller than 1 mm2. CONCLUSIONS: This study provides evidence that this multimodal approach could provide an objective tool for intra-operative assessment of breast conserving surgery margins, reducing the risk for unnecessary second operations.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Assessing Changes in the Activity Levels of Breast Cancer Patients During Radiation Therapy.

BACKGROUND: Radiation therapy (RT) is often delivered after lumpectomy for women with breast cancer. A common perceived side effect of RT is fatigue, yet its exact effect on activity levels and sleep is unknown. In this study we analyzed the change in activity levels and sleep using an activity tracking device before, during, and after RT for women with early stage breast cancer and ductal carcinoma in situ who underwent adjuvant RT. PATIENTS AND METHODS: After institutional review board approval, activity levels were quantified before, during, and after RT with measurements of steps, miles walked, calories burned, and sleep metrics in 10 women fitted with activity trackers. All data were uploaded and tabulated on a secure database. Multivariable linear regressions were used to evaluate changes in these variables over time during the RT course. RESULTS: Median step count was 5047 per day (range, 2741-15,508) and distance traveled was 1.6 miles per day (range, 0.9-5.3). Step count, distance, and calories decreased by an average of 54 steps per day, 0.02 miles per day, and 3 calories per day (median calories 1822; range, 1461-2712) during RT, respectively. These changes were statistically significant (P < .001), but not clinically relevant. There was no significant change in sleep (average 6.8 hours per night; range, 5.5-8.3). CONCLUSION: RT has a minimal effect on activity or sleep in women undergoing treatment for breast cancer. Activity levels varied greatly between patients in a population of women undergoing hypofractionated RT. Because increased activity levels correlate with improved outcomes, further studies evaluating attempts to increase physical activity during as well as after treatment with radiation are warranted.

Sentinel lymph node biopsy and aberrant lymphatic drainage in recurrent breast cancer: Findings likely to change treatment decisions.

BACKGROUND AND OBJECTIVES: It is not clear whether sentinel lymph node biopsy (SLNB) can be applied to patients with a second breast cancer or recurrence occurring at previously treated breast. The purpose of this study was to assess the feasibility of SLNB procedure in patients with recurrent breast cancer. METHODS: Patients with non-metastatic recurrent N0 breast cancer at ipsilateral breast were included. Patients were grouped according to their initial breast, axilla, and overall surgery. Presence of drainage and its pattern as well as SLNB success rate and overall axillary involvement rates were assessed. Findings were compared. RESULTS: Out of 75 patients, mean age was 52.5 years and disease-free interval was 82 (9-312) months. Lymphatic drainage was successful in 42 (56%) patients. Drainage positivity was more frequent in patients who were previously treated with SLNB (82.6%) than in patients who underwent axillary lymph node dissection (ALND) (44.2%; P = 0,002). Aberrant lymphatic drainage was detected in 64.3% of drainage positive patients. Success rate of reoperative SLNB was 92.9%. Adjuvant treatment plan was altered in 12 (16%) patients. In 15 patients, negative SLNB prevented axillary dissection. CONCLUSIONS: Reoperative SLNB seems to be technically feasible in N0 recurrent breast cancer patients. It may further avoid unnecessary ALND and lead changes in adjuvant treatment plans. J. Surg. Oncol. 2016;114:796-802. © 2016 2016 Wiley Periodicals, Inc.

Clinico-epidemiological profile of breast cancer patients and the retrospective application of Gail model 2: An Indian perspective.

AIM: To study the clinical and epidemiological profile of patients of breast cancer presenting at our center at New Delhi, India and to evaluate the applicability of Gail model 2 as a means of measuring 5-year and lifetime risk in our already diagnosed cases of breast cancer. METHODS: This was a retrospective study conducted at Lady Hardinge Medical College Hospital in New Delhi, India, between January 2011 and July 2014. Two hundred and twenty two diagnosed cases of breast cancer were included. Information was collected retrospectively on a Performa from the medical record section and the Pathology department of the hospital.The predicted five-year and lifetime risk was calculated using GM2 prediction model from the NCI's breast cancer risk assessment tool website. RESULTS AND CONCLUSIONS: Breast cancer in India is a far more biologically aggressive disease than in the west with a widely different spectrum of presentation and behavior and late presentation in an advanced stage. The accepted risk factors routinely associated with breast cancer in western literature do not appear to be relevant in the Indian population. Accepted western models do not seem to apply in the Indian scenario.

Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

Neoplasia intraductal papilar de la vía biliar: a propósito de un caso / Intraductal papillary neoplasm of the bile duct

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Cognitive, psychosocial, somatic and treatment factors predicting return to work after breast cancer treatment.

BACKGROUND: Breast cancer (BC) may affect the ability to work. In this study, we want to identify any associations between cognitive, psychosocial, somatic and treatment factors with time to return to work (RTW) among women treated for BC. METHODS AND PARTICIPANTS: At eight (baseline) and 11(follow-up) months after BC diagnosis, women who had received adjuvant treatment for early BC at Stockholm South General Hospital completed the Headminder neuropsychological tests to obtain the Cognitive Stability Index (CSI), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and its Breast Cancer Module. At both time points, we compared the scores from women who had returned to work with those who had not. We also reviewed the medical certificates of women still on sick leave at 8, 11 and 18 months after diagnosis to determine why they had not returned to work. RESULTS: At baseline, 29 of 45 enroled women were working and 15 were not (one dropped out after baseline testing). The 14 women still not working 11 months after BC diagnosis had more advanced BC (OR = 3.64, 95% CI 2.01-7.31), lymph-node involvement (OR = 18.80, 95% CI 5.32-90.69) and Her 2-positive tumours (OR = 10.42,95% CI 2.19-65.32) than did working women. None of the scores for the four cognitive domains changed significantly at follow-up in either group. Comments on the medical certificates generally supported these findings. Independently of any adjuvant cancer therapy, overall quality of life improved and most women did RTW 18 months after BC diagnosis. CONCLUSIONS: Chemotherapy is associated with longer periods of sick leave. Cognitive functions do not predict RTW. Independently of any adjuvant therapy, most women eventually RTW in a few months. The ability to predict RTW after BC treatment should help prepare higher-risk patients for delayed RTW and allow earlier interventions to restore their social relations and quality of life.

Divergent behaviour of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) in breast carcinogenesis.

AIMS: To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis. METHODS AND RESULTS: The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non-invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015). CONCLUSIONS: 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions.

Carcinoma ductal in situ de la mama: primeros 100 casos Ceclines / Ductal in situ carcinoma of breast: 100 first cases Ceclines

Describir los primeros 100 casos de carcinoma ductal in situ en nuestra institución. 100 casos tratados adoptamos la definición de mic de Silver y Tavassoli: 77 fueron puros y 23 mic. En 69 por ciento se practicó cirugía preservadora, 31 por ciento mastectomía, 24 por ciento con reconstrucción, una bilateral y 7 por ciento sin reconstrucción. 64 por ciento recibió radioterapia complementaria. 36 por ciento el tratamiento fue cirugía sola. 77 por ciento recibieron terapia hormonal adyuvante. En 46 por ciento practicamos biopsia de ganglio centinela: 25 por ciento in situ puros y 21 por ciento mic. En 83 por ciento la presentación fue micro calcificaciones. El patrón histológico cribiforme y mixtos, los más frecuentes, 75 por ciento. El tamaño mamográfico e histológico coincidieron, 20 mm, promedio. El 87 por ciento grado nuclear II o III actividad mitótica 82 por ciento fue baja o moderada sólo 4 por ciento alta. El 78 por ciento presentó necrosis. De 25 pacientes con in situ puro, que se les practicó ganglio centinela ninguna presentó enfermedad ganglionar y los 21 con in situ mic, 9,52 por ciento presentaron metástasis. 2 por ciento recaídas locales, con enfermedad infiltrante; una a 52 meses, los otros a 58 meses. Una sin radioterapia, se trataron con mastectomía de rescate. No ocurrieron muertes por enfermedad. El buen manejo de los casos, traduce satisfactorios resultados de sobre vida libre de enfermedad y sobrevida global. Podemos seleccionar un sub-grupo de pacientes a quienes les pueda omitir la radioterapia sin aumentar el riesgo de mortalidad.

Describe first 100 cases of ductal carcinoma in situ in our institution. 100 cases treated adopted the definition of mic by Silver and Tavassoli: 77 pure and 23 mic. 69 percent we performed breast conserving surgery 31 percent total mastectomy 24 percent reconstruction, 1 was bilateral, 7 percent without reconstruction. 64 percent received complementary radiotherapy. 36 percent treatment was surgery alone. 77 percent recieved hormonal adjuvant therapy. 46 percent we performed sentinel lymph node biopsy: 25 percent were pure and 21 percent mic. 83 percent initial form of presentation was micro calcifications. The histological type was cribiform and mixed (75 percent). The mammographic and histological size matched 20 mm average. 87 percent were nuclear grade II and III, 82 percent of the mitotic activity was moderate or low only 4 percent were high. 78 percent had necrosis. Out of the 25 patients with pure in which we practice none presented ganglion disease and out of the 21 patients with mic, 9.52 percent presented ganglion metastasis. 2 percent had local recurrence, both of them with invasive disease, one 52 months the other one at 58 month from surgery. One didn´t received radiation. Both were treated with rescue mastectomy. There was no death diseases related. Adequate and good management of cases results related to disease free survival and overall survival. We can classify sub group of patients in which may avoid radiation without increasing the risk of mortality.

Carcinoma ductal in situ: correlación entre la histología y la resonancia magnética de mama / Breast MRI-histologic correlation for ductal carcinoma in situ

Objetivo: Evaluar la concordancia de la resonancia magnética (RM) de mama con la histología en la valoración del tamaño y extensión del carcinoma ductal in situ puro (CDIS), y compararla con la de las técnicas convencionales (mamografía y ecografía). Material y métodos: Estudio retrospectivo de pacientes consecutivas con biopsia percutánea con resultado de CDIS. Se estimó el coeficiente de concordancia de correlación de Lin para cada uno de las 3 técnicas de imagen con la histología. Además, se revisó la concordancia con gráficos de Bland-Altman. Se evaluaron los cambios de conducta quirúrgica generados por la RM. Resultados: El grupo estudiado fue de 32 pacientes. En cuanto al tamaño tumoral, la concordancia fue superior en la RM (0,78; intervalo de confianza [IC] de 95%, 0,62–0,87) que en la mamografía (0,43; IC del 95%, 0,19–0,62) o en la ecografía (0,27; IC del 95%, 0,09–0,43). La RM sobrestimó el tamaño con un promedio de 3mm, mientras que la mamografía y la ecografía lo subestimaron en 9 y 18mm, respectivamente. La RM fue superior para la detección del multifocalidad o multicentricidad (7 casos) frente a la mamografía (3 casos) y a la ecografía (0 casos). Hubo 6 cambios de conducta quirúrgica correctos basados en los hallazgos de la RM. Conclusión: La RM de mama es superior a las técnicas convencionales en la valoración del tamaño de los CDIS. Además, detecta más casos de multifocalidad y multicentricidad, por lo que aconsejamos su utilización prequirúrgica en pacientes diagnosticadas de CDIS, especialmente en mamas densas (AU)

Objective: To evaluate the concordance between the breast MRI findings and the histologic findings for the size and extension of pure ductal carcinoma in situ (DCIS) and to compare this concordance with that of conventional techniques (mammography and ultrasonography). Material and methods: This is a retrospective study of consecutive patients diagnosed with DCIS after percutaneous biopsy. We estimated Lin's coefficient of concordance for the histologic findings with each of the three techniques. We also assessed concordance using Bland-Altman graphs. Finally, we determined the impact of the MRI findings on the surgical management of patients with DCIS. Results: A total of 32 patients were included in the study. Concordance between imaging and histology on tumor size was higher for MRI (0.78; 95%CI, 0.62–0.87) than for mammography (0.43; 95%CI, 0.19–0.62) or for ultrasonography (0.27; 95%CI, 0.09–0.43). MRI overestimated the size of DCIS by a mean of 3mm, whereas mammography and ultrasonography underestimated it by 9mm and 18mm, respectively. MRI detected multifocality and multicentricity (7 cases) better than mammography (3) or ultrasonography (0). The MRI findings correctly changed the surgical management in six patients. Conclusion: Breast MRI is better than conventional techniques for the evaluation of the size of DCIS. Breast MRI also detects more cases of multifocality and multicentricity. We recommend that all patients diagnosed with DCIS (especially those with dense breasts) undergo breast MRI prior to surgery (AU)

Characterization of high-grade ductal carcinoma in situ with and without regressive changes: diagnostic and biologic implications.

Regressive changes (RC) have been described in malignant melanoma, carcinomas of the prostate and cervix. The presence of RC in these neoplasms may signify some degree of host response to tumor and seems to be a sign of poor prognosis for some neoplasms. RC in breast cancer is vaguely defined in the older literature. We have observed periodically similar RC in a subset of high-grade ductal carcinoma in situ (HGDCIS) in breast specimens. The aim of our study is to demonstrate how to recognize RC in the diagnostic setting and an attempt to understand the biologic behavior in this subset of HGDCIS cases. Fifty-nine cases of HG-DCIS (35 cases with RC and 24 cases without RC) were included. We defined RC in our study as demonstrating thick periductal fibrosis, dense lymphocytic infiltrate, and a thin rim of intact neoplastic cells. A short panel of immunomarkers to study this entity included myoepithelial markers. Reduced expression of myoepithelial markers (p63 and smooth muscle heavy chain myosin) were seen more frequently in the HGDCIS group with RC than without RC cases. Invasion as well as metastatic disease was seen in association with HGDCIS with RC nearly 4 times as often. It is also critically important to recognize HGDCIS-RC for diagnostic purposes, as the differential diagnosis of RC includes, benign associations such as papilloma, fibrocystic changes and periductal mastitis. HGDCIS-RC may also be a sign of an aggressive phenotype than other HGDCIS subtypes. Further outcome studies are necessary to determine if it has a clinical impact akin to other tumors with RC.

Computational model of ductal carcinoma in situ: the effects of contact inhibition on pattern formation.

The computational model presented in this paper focuses on modeling ductal carcinoma in situ (DCIS), which is the most commonly detected preinvasive form of breast cancer. The model aims to understand the biological mechanisms and resultant growth dynamics of DCIS. The cellular automaton model based on observed phenotypic characteristics of DCIS emphasize the important role of contact inhibition on lesion pattern formation. Computer simulations resembled the cribriform, micropapillary, solid, and comedo patterns of DCIS. The model has led to insights about the progression of the preinvasive disease such as possible explanations for coexisting micropapillary and cribriform patterns commonly found through histological analyses.

Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution.

PURPOSE: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs. EXPERIMENTAL DESIGN: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes. RESULTS: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007). CONCLUSIONS: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.