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.
Human tumors are stiff and data suggest that the extracellular matrix stiffening is consistent with experimental mammary tumor models in which stiffness drives tumor invasion and metastasis.
Worsening of respiratory mechanics during a spontaneous breathing trial (SBT) has been traditionally associated with weaning failure, although this finding is based on studies with chronic ...obstructive pulmonary disease patients only. The aim of our study was to assess the course of respiratory impedance non-invasively measured by forced oscillation technique (FOT) during a successful and failed SBT in a mixed population.
Thirty-four weaning trials were reported in 29 consecutive mechanically ventilated patients with different causes of initiation of ventilation. During the SBT, the patient was breathing through a conventional T-piece connected to the tracheal tube. FOT (5 Hz, ± 1 cm H2O, 30 s) was applied at 5, 10, 15, 20, 25, and 30 min. Respiratory resistance (Rrs) and reactance (Xrs) were computed from pressure and flow measurements. The frequency to tidal volume ratio f/Vt was obtained from the flow signal. At the end of the trial, patients were divided into two groups: SBT success and failure.
Mixed model analysis showed no significant differences in Rrs and Xrs over the course of the SBT, or between the success (n=16) and the failure (n=18) groups. In contrast, f/Vt was significantly (P<0.001) higher in the failure group.
Worsening of respiratory impedance measured by FOT is not a common finding during a failed SBT in a typically heterogeneous intensive care unit population of mechanically ventilated patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
The Breast Cancer Surveillance Consortium (BCSC) model is a widely used risk model that predicts 5- and 10-year risk of developing invasive breast cancer for healthy women aged 35–74 years. ...Women with high BCSC risk may also be at elevated risk to develop interval cancers, which present symptomatically in the year following a normal screening mammogram. We examined the association between high BCSC risk (defined as the top 2.5% by age) and breast cancers presenting as interval cancers.
Methods
We conducted a case-case analysis among women with breast cancer in which we compared the mode of detection and tumor characteristics of patients in the top 2.5% BCSC risk by age with age-matched (1:2) patients in the lower 97.5% risk. We constructed logistic regression models to estimate the odds ratio (OR) of presenting with interval cancers, and poor prognosis tumor features, between women from the top 2.5% and bottom 97.5% of BCSC risk.
Results
Our analysis included 113 breast cancer patients in the top 2.5% of risk for their age and 226 breast cancer patients in the lower 97.5% of risk. High-risk patients were more likely to have presented with an interval cancer within one year of a normal screening, OR 6.62 (95% CI 3.28–13.4,
p
< 0.001). These interval cancers were also more likely to be larger, node positive, and higher stage than the screen-detected cancers.
Conclusion
Breast cancer patients in the top 2.5% of BCSC risk for their age were more likely to present with interval cancers. The BCSC model could be used to identify healthy women who may benefit from intensified screening.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background: At the UCSF breast screening clinic, intake surveys are sent to women with upcoming mammogram appointments to obtain their demographic data, comorbidities, and assess breast ...cancer risk (family history, biopsy history). Many patients complete surveys online before their visit. For those who do not, a staff member is present to assist with survey completion on a tablet in-clinic.
Methods: Data was collected from 10,755 patients from December 2012–May 2018. To assess if different survey modalities capture different demographic groups, we analyzed these submissions, comparing responses completed by patients online before visits and in-clinic with assistance.
Results:On average, 48% of invited patients complete a survey. Of respondents 76% completed surveys before visits and 24% completed surveys in-clinic. Both methods captured electronic data that was summarized and presented to clinicians for clinical decision support. Compared to the in-clinic group, a before group patient was more likely to be white, married, and have at least a college education. The before group included a smaller proportion of patients who were Black/African American, Hispanic/Latina, and 65 years or older. Furthermore, a greater proportion of the before group reported 2 or more comorbidities. The before population reported more often having fair or poor health over the preceding 30 days. While these differences were statistically significant, it is important to put some of these results into perspective: while only 24% of survey responses were collected in-clinic, 59.1% of all Black/African American responses and 33.5% of all Hispanic/Latina responses were represented in this group.
Before group (N=7869) In-clinic group (N=2886)P valueWhite64.43%55.79%<0.0001Black/African American3.57%10.91%<0.0001Hispanic/Latina7.96%10.91%<0.0001Aged 65 or older29.84%39.54%<0.0001Married66.40%56.10%<0.0001College educated or more79.93%66.87%<0.00012 or more diagnosed comorbidities38.18%30.32%<0.0001Poor or Fair health over last 30 days10.41%5.45%<0.0001
Conclusions/Future Directions: 1) Online surveys are completed more often by traditionally well-represented groups. Offering staff supported electronic surveys in-clinic improves the total yield and diversity of patients who complete surveys. More research is required to see the impact of income levels. 2) We did not anticipate a greater incidence of fair or poor health over the last 30 days or the higher number of patients reporting 2 or more comorbidities in the before group. This could result from the before group having better access to health care, and more familiarity with health surveys, but more detailed study is needed. 3) We will investigate further issues of health care trust, familiarity, and access to adjust our clinic practices. As more studies move surveys entirely online, we need to identify and address factors that prevent patients from completing surveys before appointments. Alternative survey modalities must be made available in accessible ways and integrated into routine clinical practice.
Citation Format: Shibley WP, Dreher N, van 't Veer L, Acerbi I, Fiscalini AS, Keane H, Esserman LJ, Athena Breast Health Network Investigators and Advocate Partners. Comparing characteristics of patients who fill out online surveys before visits with patients who fill out surveys in-clinic with staff assistance at the UCSF breast screening clinic abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-17.
Abstract
Background: Smoking is a known risk factor for various types of cancer, and breast cancer patients who smoke are known to have higher breast cancer mortality. However, few studies have found ...an association between smoking and breast cancer incidence or tumor biology. The Athena Breast Health Network distributes an intake questionnaire at the UCSF and UCSD breast care centers which can be used to investigate links between tobacco exposure and the characteristics of incident breast cancer.
Methods: Intake questionnaires were distributed to all new patients at the UCSF and UCSD breast care centers from December 2012 to May 2018. Patients who completed the questionnaire with a known diagnosis of breast cancer were compared to those without in a case-control study. Breast cancer diagnoses were determined by ICD9 diagnosis codes from the patients' medical records. The association of smoking and breast cancer prevalence and biology was analyzed using generalized linear models and Fisher tests in R.
Results: Of the 7727 patients who completed the Athena intake questionnaire at UCSF and UCSD, 5499 consented to have their data used for research. A first analysis was conducted on 4175 UCSF patients alone: 2186 of the UCSF patients who had completed the questionnaire had a documented breast cancer diagnosis, vs 1989 with no known diagnosis at the time of this analysis. 1096 of the 4175 UCSF patients reported having ever smoked, including 73 who had accrued 30 or more pack years. Complete pathology data was available for 1120 cancer patients. Controlling for age, more patients with invasive breast cancer reported having ever smoked, with an odd's ratio (OR) of 2.32 (p = .0043). By including DCIS, the OR drops slightly to 2.26 (p = .0058). Taking alcohol consumption into account as a confounder lowered the OR to 2.19 (p = .0454). Overall, the risk of breast cancer increases with each additional pack year (OR = 1.08, p = .0211), independent of age. There are no significant differences in tumor biology for any smoking group.
Conclusions: A history of smoking is associated with an increased risk of developing breast cancer and is directly related to cumulative pack years exposure. This association should be further validated in cohort studies.
Citation Format: Dreher N, Layton TM, Parker BA, Shibley WP, Acerbi I, Wallace AM, Blair S, Pierce JP, Glantz S, Guydish J, Hiatt R, van 't Veer L, Esserman L, Athena Breast Health Network Investigators and Advocate Partners. Tobacco exposure and breast cancer abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-03.
Abstract
Purpose: Women Informed to Screen Depending on Measures of risk (WISDOM) trial is a pragmatic study comparing two real world approaches to clinical care for breast screening: annual ...screening versus personalized screening. The novelty of the personalized arm of the study is that we are combining known risk factors (age, family history, history of breast disease, ethnicity, BIRADS breast density, and genetics) into a single risk assessment model. All components of the model have been tested and established, but have never been used jointly.
The goal of the WISDOM study is to examine the effectiveness of personalized breast cancer screening and to bring objective recommendations to the current mammography screening debate.
Methods: The WISDOM trial will enroll 100,000 women with a preference-tolerant design that will determine if risk-based screening vs. annual screening, is as safe, less morbid, enables prevention, and is preferred by women. Women 40 - 74 years of age with no history of breast cancer or DCIS, and no previous double mastectomy can join the study from the WISDOM Study website (wisdomstudy.org). All participants sign up, elect randomization or self-select the study arm, provide electronic consent using DocuSign (eConsent), and sign a Medical Release Form. For all participants, 5-year risk of developing breast cancer is calculated according to the Breast Cancer Screening Consortium (BCSC) model. For participants in the personalized arm, the overall 5-year risk BCSC score is combined with a Polygenic Risk Score, based on a genetic test including mutations in 9 genes (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, ATM, PALB2, and CHEK2) and a panel of 75 common single nucleotide polymorphisms known to increase breast cancer risk. Risk stratification will determine frequency of screening. The study is registered on ClinicalTrials.gov as NCT02620852.
Results: As of June 12th 2017, the WISDOM study is live at all UC medical centers and recruitment is open to all eligible women in California. Up to date 4,769 eligible women registered at all sites. 2,823 women have consented in the trial. 64% were randomized and 36% chose their screening arm. A pilot was conducted to test the logistics of online participation and examine the acceptance of the study design and approach. We are partnering with health insurance companies and self-insured companies to reach our recruitment goal.
Conclusions: Enrollment will be completed by end of 2018.
Acknowledgment: support by the Patient-Centered Outcomes Research Institute (PCORI), PCS-1402-10749 to L.J.E.
(*) Authors equally contributed to this work.
Citation Format: Acerbi I, Abihider K, Ling J, Layton T, DeRosa D, Madlensky L, Tice J, Shieh Y, Ziv E, Sarrafan S, Firouzian R, Tong B, Blanco A, Lee V, Heditsian D, Brain S, Kaplan C, Borowsky A, Anton-Culver H, Naeim A, Cink T, Stover Fiscalini A, Parker B, van 't Veer L, Wisdom Study and Athena Breast Health Network Investigators and Advocate Partners, LaCroix A, Esserman L. Preference-Tolerant randomized trial of risk-based vs. annual breast cancer screening: WISDOM study in progress abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-03-01.
Abstract
Background: WISDOM is a 100,000 healthy women preference-tolerant, pragmatic study comparing annual to personalized risk-based breast screening. The novelty of WISDOM personalized screening ...is the integration of previously validated genetic and clinical risk factors (age, family history, breast biopsy results, ethnicity, mammographic density) into a single risk assessment model that directs the starting age, timing, and frequency of screening. The goal of WISDOM is to determine if personalized screening, compared to annual screening, is as safe, less morbid, enables prevention, and is preferred by women. The study is registered on ClinicalTrials.gov, NCT02620852.
Methods: Women aged 40-74 years with no history of breast cancer or DCIS, and no previous double mastectomy can join the study online at wisdomstudy.org. Participants can elect randomization or self-select a study arm, and provide electronic consent and Release for Medical Information using DocuSign. For all participants, 5-year risk of developing breast cancer is calculated according to the Breast Cancer Screening Consortium (BCSC) model. Participants in the personalized arm undergo panel-based mutation testing, and their 5-year risk is calculated using the BCSC score combined with a Polygenic Risk Score (BCSC-PRS) that includes 75 single nucleotide polymorphisms (SNPs, increase to 229) known to increase breast cancer risk. SNPs and mutations (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, ATM, PALB2, and CHEK2) are assessed by saliva-based testing through Color Genomics. 5-year risk level thresholds are used to stratify for low-, moderate- and high risk. Risk stratification determines age to start, stop, and frequency of screening.
Enrollment: As of July 2018, the WISDOM study is open to all eligible women in California, North Dakota, South Dakota, Minnesota and Iowa. To date, 23,329 eligible women have registered and 14,393 women have consented to participate in the trial. We analyzed 3,255 participants who have completed risk assessment in the personalized arm. The median age was 56 years. 82% were Caucasian, 1% African-American, and 6% Asian. 9% self-reported as Hispanic. We are partnering with health insurers and self-insured companies using coverage with evidence progression. To strengthen generalizability, we are expanding to other states. WISDOM enrollment will continue past 2019.
Feasibility: To evaluate the addition of PRS, we used paired statistical tests (McNemar) to compare the distributions of BCSC, and BCSC-PRS risk estimates around low-risk (<1.3%), and very-high risk (>6%) thresholds, the latter corresponding to 5-year risk of a BRCA mutation carrier. The median 5-year risk was 1.5% (IQR 1.0-2.1%) using the BCSC model, and 1.4% (IQR 0.8-2.5%) using the BCSC-PRS model. The BCSC-PRS model classified more women into the low (<1%) and very high (≥6%) risk categories compared to the BCSC model (p < 0.001).
Conclusions: Our findings demonstrate that incorporating genetic variants into a validated clinical model is feasible and impacts risk classification compared to a model without genetic risk factors. Results at 5 years will reveal if this classification improves healthcare value by reducing screen volumes and costs without jeopardizing outcomes.
Citation Format: Acerbi I, Shieh Y, Madlensky L, Tice J, Ziv E, Eklund M, Blanco A, DeRosa D, Tong B, Goodman D, Nassereddine L, Anderson N, Harvey H, Layton T, Park HL, Petruse A, Stewart S, Wernisch J, Risty L, Koenig B, Sarrafan S, Firouzian R, Kaplan C, Hiatt R, Parker BA, Wenger N, Lee V, Heditsian D, Brain S, Stover Fiscalini A, Borowsky AD, Anton-Culver H, Naeim A, Kaster A, Talley M, van 't Veer LJ, LaCroix A, Wisdom Study and Athena Breast Health Network Investigators and Advocate Partners, Esserman LJ. Personalized breast cancer screening in a population based study: Women Informed to Screen Depending On Measures of risk (WISDOM) abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-08-01.
Abstract
Introduction: Mammographic density (MD) is associated with greater risk to malignancy. MD is also correlated to high collagen content in the extra cellular matrix (ECM). Data from our group ...and others have highlighted the importance of mechanical cues from the ECM in breast tissue homeostasis and tumor progression to invasion 1; 2; reviewed in 3. Whether the stiffness of the ECM could also initiate breast cancer and if so how remains unknown. Because elevated collagen levels increases ECM stiffness, we hypothesize that MD increases breast cancer risk because the ECM is stiffer. Materials and Methods: We studied breast tissues obtained through prophylactic mastectomy from women with low (BIRADS 1) versus high MD (BIRADS 4). From each surgically excised breast, samples of 0.5cm x 0.5cm x 1cm dimension were removed from the retroareolar region and from 4 peripheral quadrants. Sample sections were subjected to biophysical, morphological and biochemical analysis. Biophysical analysis included the application of Atomic Force Microscopy to obtain an extensive force map of distinct anatomical regions of the ECM associated with the intra-lobular and inter-lobular ECM. Topological analysis of ECM architecture was performed using two photons and SIM-POL imaging coupled with picrosirius staining, polarized light imaging and image quantification. Biochemical and morphological analysis consisted of immunohistochemistry for markers that detect mechano-signaling in the epithelium and stromal fibroblasts, and H&E to visualize cellular and ECM organization.
Results and Discussion: We found that the intra-lobular ECM associated with the terminal end-buds in the breast contained anisotropic relaxed collagen fibrils and was very compliant. By contrast, the inter-lobular ECM of the breast contained oriented collagen fibrils and was relatively stiffer. Notably, the ECM associated with the retroareolar region, which is typically detected as very dense using mammographic imaging, contained oriented collagen fibrils, and was significantly stiffer than the ECM associated with the peripheral quadrants. Intriguingly, preliminary data suggested that the ECM associated with the terminal end-buds in the upper outer quadrant showed a trend towards greater stiffness in women with high MD (BIRADS 4) than low MD (BIRADS 1). Although, it is tempting to speculate that ECM stiffness could enhance risk to malignancy, further sample analysis is now necessary.
Conclusions: • In the human breast there is anatomical heterogeneity with respect to ECM organization and mechanical properties.
High MD appears to reflect elevated ECM stiffness. The intra-lobular ECM is considerably stiffer in the upper outer quadrant than in the other peripheral regions of the breast. Atomic Force Microscopy is a tractable method to monitor ECM stiffness and mechanical heterogeneity in the human breast.
Acknowledgements: supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC, U54CA143836-01 to JL and VW.
References:
1. Paszek et al., Cancer, Cell 8:241–254, 2005
2. Levental et al., Cell, 139: 891–906 2009
3. Yu et al., Trends Cell Biol, 21(1):47–56, 2010
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-10-01.
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