Cindy B. Matsen

Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes

Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.

Breast cancer: a review for the general surgeon.

Breast cancer care is complex and requires a multidisciplinary approach. In this study, we provide an overview of current practices for the diagnosis and treatment of breast cancer for surgical practitioners who do not focus on this disease. We include studies published in high-impact, peer-reviewed journals that have informed or altered the standard of care, with preference given to large, multicenter, randomized clinical trials when available. Our study highlights that the surgical management of breast cancer has changed dramatically over the past decades. As our understanding of the disease process increases, practice guidelines will continue to evolve.

Overview of Human Primary Tumorgraft Models: Comparisons with Traditional Oncology Preclinical Models and the Clinical Relevance and Utility of Primary Tumorgrafts in Basic and Translational Oncology Research

Laboratory models that accurately replicate human tumor initiation and characteristics are integral to advancing knowledge in cancer research. However, comparative studies between commonly employed laboratory models and human tumors have demonstrated that some models have molecular and genomic alterations dissimilar to the cancer type they attempt to replicate. In contrast, several recent comparative studies suggest that because patient‐derived tumors grown in mice maintain many of the important characteristics of the original tumor, they represent an important tool for the development of new cancer therapeutics. Detailed in this overview are the advantages and disadvantages of the most commonly used cancer models for mechanistic and therapeutic research, with an emphasis on the advances made in the production and use of patient‐derived tumorgrafts. Curr. Protoc. Pharmacol. 59:14.22.1‐14.22.9.

Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells

IntroductionHigh failure rates of new investigational drugs have impaired the development of breast cancer therapies. One challenge is that excellent activity in preclinical models, such as established cancer cell lines, does not always translate into improved clinical outcomes for patients. New preclinical models, which better replicate clinically-relevant attributes of cancer, such as chemoresistance, metastasis and cellular heterogeneity, may identify novel anti-cancer mechanisms and increase the success of drug development.MethodsMetastatic breast cancer cells were obtained from pleural effusions of consented patients whose disease had progressed. Normal primary human breast cells were collected from a reduction mammoplasty and immortalized with human telomerase. The patient-derived cells were characterized to determine their cellular heterogeneity and proliferation rate by flow cytometry, while dose response curves were performed for chemotherapies to assess resistance. A screen was developed to measure the differential activity of small molecules on the growth and survival of patient-derived normal breast and metastatic, chemoresistant tumor cells to identify selective anti-cancer compounds. Several hits were identified and validated in dose response assays. One compound, C-6, was further characterized for its effect on cell cycle and cell death in cancer cells.ResultsPatient-derived cells were found to be more heterogeneous, with reduced proliferation rates and enhanced resistance to chemotherapy compared to established cell lines. A screen was subsequently developed that utilized both tumor and normal patient-derived cells. Several compounds were identified, which selectively targeted tumor cells, but not normal cells. Compound C-6 was found to inhibit proliferation and induce cell death in tumor cells via a caspase-independent mechanism.ConclusionsShort-term culture of patient-derived cells retained more clinically relevant features of breast cancer compared to established cell lines. The low proliferation rate and chemoresistance make patient-derived cells an excellent tool in preclinical drug development.

In the Modern Treatment Era, Is Breast Conservation Equivalent to Mastectomy in Women Younger Than 40 Years of Age? A Multi-Institution Study

PURPOSE Mastectomy is often recommended for women ≤40 years of age with breast cancer, as young women were under-represented in the landmark trials comparing breast conservation therapy (BCT) to mastectomy. We hypothesized that, in the modern treatment era, BCT and mastectomy result in equivalent local control rates in young women. METHODS AND MATERIALS Breast cancer cases arising between 1975 and 2013 in women ≤40 years old were collected from the tumor registries of 2 large healthcare systems in Utah. Kaplan-Meier estimates and Cox proportional hazards models were used to analyze freedom from locoregional recurrence (FFLR), overall survival (OS), and relapse-free survival (RFS). RESULTS This analysis identified 853 BCT candidates. A comparison of BCT to mastectomy after 2000 showed FFLR, RFS, and OS were all similar. Rate for FFLR at 10 years was 94.9% versus 92.1% for BCT and mastectomy, respectively (P=.57). For women whose cancer was diagnosed after 2000, who received BCT, FFLR and RFS rates were improved compared to those whose cancer was diagnosed prior to 2000 (P<.05), whereas OS (P=.46) rates were similar. Among those who underwent mastectomy, FFLR, OS, and RFS were significantly improved (P<.05) with diagnosis after 2000. CONCLUSIONS FFLR rates for young women, ≤40 years of age, have significantly improved for BCT and mastectomy over time. If patients were treated after 2000, BCT appears to be safe and equivalent to mastectomy at 10 years in terms of FFLR, OS, and RFS.

Breast cancer screening of pregnant and breastfeeding women with BRCA mutations.

Screening recommendations for women with BRCA mutations include annual breast MRI starting at age 25, with annual mammogram added at age 30. The median age of childbearing in the US is age 28, therefore many BRCA mutation carriers will be pregnant or breastfeeding during the time when intensive screening is most important to manage their increased breast cancer risk. Despite this critical overlap, there is little evidence to guide clinicians on the appropriate screening for women with BRCA mutations during pregnancy or breastfeeding. Hormonal shifts that occur during pregnancy, the postpartum period, and breastfeeding result in changes to the breasts that may further complicate the sensitivity and specificity of screening modalities. We explore the safety and efficacy of available breast cancer screening modalities, including clinical breast exam, mammogram, breast MRI, and ultrasound among women with BRCA mutations who are pregnant or breastfeeding, providing recommendations from the most current published literature and expert opinion.

A match made in heaven? Trying to combine ACS-NSQIP and NCDB databases.

BACKGROUND As part of a larger study evaluating breast cancer care, we attempted to validate our matching strategies between the National Cancer Data Base (NCDB) and ACS National Surgical Quality Improvement Program (ACS-NSQIP). METHODS Using 2002-2006 data, we attempted to match cases by a three-tiered approach. Three groups resulted: (1) successfully matched, (2) NCDB case with no corresponding match in ACS-NSQIP, and (3) ACS-NSQIP case with no match in NCDB. Single institution (University of Utah) data were used for a nested validation study of the unmatched groups. RESULTS The initial match yielded a 23.4% net match rate (rate of 8.6% at the University of Utah). In subset review of unmatched University of Utah cancer registry cases (NCDB, n = 153), 56% (n = 86) of cases had their index surgery at the University of Utah, with 15 potential matches in the unmatched ACS-NSQIP data using age and date of surgery and no potential match for 41 cases. Twenty-five remaining cases had a potential surgery date match if age was varied by 1 y with 18 confirmed matches. Review of unmatched ACS-NSQIP cases (n = 107) yielded 15 potential matches in the University of Utah cancer registry, with no potential match for 63 cases. Twenty-nine cases had a potential surgery date match if age was varied, with 26 confirmed matches. Review of ACS-NSQIP cases from 2006 for cancer status and stage revealed two cancer patients who were not in the cancer registry. CONCLUSIONS Linking ACS-NSQIP and NCDB without a captive patient population results in low overall match rates due, in part, to specific inclusion criteria and different variable definitions for each database.

Decision role preferences for return of results from genome sequencing amongst young breast cancer patients

OBJECTIVE To better understand decision role preferences in women diagnosed with breast cancer at a young age for return of results of genome sequencing in research and clinical settings. METHODS Participants were surveyed about communication and decision-making preferences related to genome sequencing results and factors that may affect these preferences. The primary outcome was decision role preference (Control Preference Scale) for selecting what results to receive within medical care or within a research study. RESULTS For results returned as part of medical care, most patients preferred a collaborative (N = 481, 45%) or active (N = 488, 45%) role with only 107 (10%) choosing a passive role. When making the decision as part of a research study, most patients preferred an active role (N = 617, 57%), 350 (33%) choosing a collaborative role, and110 (10%) choosing a passive role. CONCLUSION Most women in this study preferred to share in decision making. Participants had somewhat different role preferences for clinical and research contexts, with greater preference for active roles in the research context. PRACTICE IMPLICATIONS We advocate for practice guidelines that incorporate discussion of decision role as an integral part of patient centered care and shared decision-making and recognize that more work is needed to inform guidelines.

High-frequency (10-100 MHz) ultrasound instrumented forceps for precision cancer surgery

A critical issue for surgery of soft tissue cancers is ensuring removal of all malignant tissue while conserving as much unaffected tissue as possible. A minimally invasive, in vivo technique for detecting residual cancer in surgical margins or metastatic cancer in lymph nodes would significantly improve the precision and efficacy of cancer surgery. The objective of this project was to develop ultrasound instrumented “smart” forceps to guide surgeons during operations, to provide instant diagnostic information, and to enable more precise and complete resection of malignant tissue. The device was based on Martin forceps, modified to include two ultrasonic sensors (polyvinylidene difluoride) at the tips of the forceps, a tissue thickness sensor (rotary potentiometer), sensor wires, and a spring to control the manual stiffness of the forceps. A high-frequency pulser-receiver was used to excite the transmitting sensor at 50 MHz and amplify through-transmission signals from the receiving sensor. The forceps were tested with agarose phantoms embedded with polyethylene microspheres of different diameters (58-550 μm) to vary attenuation. Testing included standard 50-MHz immersion transducers for comparison. The results showed that the forceps’ performance was equal to standard transducers, with comparable sensitivity for attenuation and superior accuracy for wave speed.A critical issue for surgery of soft tissue cancers is ensuring removal of all malignant tissue while conserving as much unaffected tissue as possible. A minimally invasive, in vivo technique for detecting residual cancer in surgical margins or metastatic cancer in lymph nodes would significantly improve the precision and efficacy of cancer surgery. The objective of this project was to develop ultrasound instrumented “smart” forceps to guide surgeons during operations, to provide instant diagnostic information, and to enable more precise and complete resection of malignant tissue. The device was based on Martin forceps, modified to include two ultrasonic sensors (polyvinylidene difluoride) at the tips of the forceps, a tissue thickness sensor (rotary potentiometer), sensor wires, and a spring to control the manual stiffness of the forceps. A high-frequency pulser-receiver was used to excite the transmitting sensor at 50 MHz and amplify through-transmission signals from the receiving sensor. The forceps we...

Is radiation indicated for young women with early stage, node‐negative breast cancer after mastectomy? A multi‐institution, retrospective review

The role of post‐mastectomy radiation for women with node negative, early stage disease is not well‐defined. The purpose of this study is to more clearly define a subset of women who are ≤40 years of age with T1‐T2, node negative breast cancer who may benefit from post‐mastectomy radiation. Using tumor registries at two institutions, we identified 219 women ≤40 years of age with T1‐T2, node negative breast cancer treated with mastectomy. Of these 219 patients, 38 received post‐mastectomy radiation and 181 did not. Kaplan–Meier methods and cox proportional‐hazards regression models were employed for statistical analysis. There were no locoregional failures in the women receiving post mastectomy radiation, which lead to a nonsignificant increase in freedom from locoregional recurrence (P=.08). For women not receiving post‐mastectomy radiation, freedom from locoregional recurrence was 94.7% and 89.7% at 5‐ and 10‐years. Lymphovascular space invasion (LVSI) was the only factor predictive of locoregional recurrence. For women without LVSI, freedom from locoregional recurrence was 96.0% and 93.3% at 5‐ and 10‐years respectively. For women with LVSI who did not receive post mastectomy radiation, freedom from locoregional recurrence was 89.1% at 5‐years. There were no failures in the women with LVSI who received post mastectomy radiation. For women ≤40 years of age with T1‐2, node negative breast cancer treated with mastectomy and no post‐mastectomy radiation, locoregional control is excellent in the absence of LVSI, regardless of other risk factors. In the presence of LVSI (regardless of other risk factors), the risk of locoregional recurrence is high and appears to be decreased with post‐mastectomy radiation.