Scientific Accomplishments

> Epidemiology and Etiology
> Cancer Prevention, Risk Models, and Early Detection
> Genetics and Biology of Cancer Progression
> New Therapeutic Targets and Approaches
> Outreach, Clinical Care Delivery, and Outcomes

Theme 1: Epidemiology and Etiology

Drs. Bob Hiatt, Dejana Braithwaite, Mark Moasser, Zena Werb, Alan Balmain (Developmental Therapeutics, Cancer Genetics Programs), advocate Janice Barlow, and collaborators are leading investigators of the NIH-funded Breast Cancer and the Environment Research Program Coordinating Center. They took a transdisciplinary approach with experts from relevant fields to develop a conceptual model that yielded new insights on the etiologic factors involved in postmenopausal breast cancer. Modification of factors at a population level only modestly affected risk estimates, while it still had an important impact on the absolute number of women affected (Hiatt et al., Cancer Epidemiol Biomarkers Prev, 2014).

Theme 2: Cancer Prevention, Risk Models, and Early Detection

The Athena Breast Health Network (Dr. Laura Esserman, network PI; Dr. van ‘t Veer, site PI), an initiative of the five University of California medical centers and the South Dakota Sanford Health system, has enrolled over 85,000 women undergoing routine screening mammography into a PCORI-funded Personalized Breast Screening randomized trial using a risk-based approach (Esserman et al., Lancet Oncol, 2014; Kerlikowske et al., Evid Based Med, 2014). Drs. Esserman, van ‘t Veer, Hiatt, Nola Hylton, Celia Kaplan, Karla Kerlikowske, Britt-Marie Ljung, Michelle Melisko, John Shephard, Beth Crawford, Martin Eklund, Bonnie Joe, and Dorota Wisner are lead investigators. The risk-based screening trial will include risk thresholds based on hormonal risk factors and breast density, as well as carriership of genetic susceptibility loci ranging from high-risk BRCA1 and BRCA2 to low-moderate increased SNPs.

A number of publications substantiating the need for the comparison-effectiveness study were published in 2014. Dr. Kerlikowske and colleagues published that digital mammography leads to higher mammography screening costs without appreciable clinical benefit (Kerlikowske et al., J Natl Cancer Inst, 2014). Dr. Esserman, with fellows Eklund and O’Donoghue, evaluated the aggregate cost of mammographic screening and compared the costs to policy recommendations by professional organizations (Eklund et al., Ann Intern Med, 2014). They developed a model to estimate the cost of mammography screening in 2010, and found this cost to be $7.8 billion in the United States, with approximately 70% of women screened. The largest drivers of cost (in order) were screening frequency, percentage of women screened, cost of mammography, percentage of women screened with digital mammography, and percentage of mammography recalls. Drs. Esserman, van ‘t Veer, Kerlikowske, and Hylton looked into the imaging and biological features of low-risk and HER2 tumors, to enhance the specificity of the screening approaches and the tumor types they detect (Drukker et al., Breast Cancer Res Treat, 2014; Elias et al., Cancer Epidemiol Biomarkers Prev, 2014). In particular, mammography has a tendency to detect ultra-low risk tumors.

Theme 3: Genetics and Biology of Cancer Progression

Dr. Thea Tlsty found that fibroblast/stromal responses, such as reduced adipocytes and increased extracellular matrix content, are observed not only in tumor tissues but also in disease-free breast tissues at high risk for developing cancer, especially high-mammographic-density tissues. These results provided new insights into how high mammographic density arises and why it is associated with breast cancer risk, with implications for the definition of novel invention targets (e.g., activin A and CD36) to prevent breast cancer (DeFilippis et al., Cancer Res, 2014).

Dr. Valerie Weaver revealed that tissue mechanics of the microenvironment modulate microRNA-dependent PTEN expression to regulate malignant progression (Mouw et al., Nat Med, 2014), and that cancer cellular glycocalyx mechanically drives integrin clustering and thus primes integrin-mediated growth and survival (Paszek et al., Nature, 2014).

Drs. Keith Mostov and Zena Werb revealed another aspect of microenvironment contribution to epithelial cell polarity and proposed a molecular switch for the orientation of epithelial cell polarization. Defects in extracellular matrix (ECM) signaling led to inverted polarity, such that the apical surfaces face the surrounding ECM. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface, thereby controlling the collective orientation of epithelial polarization (Bryant et al., Dev Cell, 2014).

Dr. Jayanta Debnath showed that autophagy plays an essential role in promoting invasion, and that intact autophagy is required for the elaboration of multiple secreted factors favoring invasion, including IL-6 (Lock et al., Cancer Discov, 2014).

Program senior computational scientists Christina Yau and Denise Wolf (with Drs. van ’t Veer, Chris Benz, and Eric Collisson) took all The Cancer Genome Atlas (TCGA) data across all cancer organ types and showed, in a ground-breaking publication, that basal breast cancer is closely related to squamous carcinoma of lung or head and neck and share many features of basal signaling. Shared cancer immune modules are good prognosis features for triple-negative breast cancer. Overall, based on this study, one in ten cancer patients would be classified differently by this new molecular taxonomy versus our current tissue-of-origin tumor classification system (Hoadley et al., Cell, 2014). Methodology of this TCGA study was a follow-up of the computational scientists’ (with van ‘t Veer) publication on gene co-expression modules as clinically relevant hallmarks of breast cancer diversity (Wolf et al., PLoS One, 2014).

Drs. John Park and Hope Rugo with the NCI Translational Breast Cancer Research Consortium (TBCRC) designed an elegant way to monitor circulating tumor cells in metastatic triple-negative breast cancers by using specific enrichment strategies (Magbanua et al., Clin Cancer Res, 2015). International fellow Linda Lindstrom (with van ‘t Veer), in a prime example of team science under the Breast Cancer Association Consortium (BCAC), showed that genetic variation of the 2q36.3 chromosomal locus is associated with prognosis for estrogen receptor-negative breast cancer patients treated with chemotherapy (Zheng et al., Cell Rep, 2014).

Theme 4: New Therapeutic Targets and Approaches

Drs. Kevin Shokat (Developmental Therapeutics, Cancer Genetics Programs), Sourav Bandyopadhyay (Associate Member), and Andrei Goga took an innovative approach to link tumor mutations across multiple cancer cell lines, including breast cancer, to drug responses via a quantitative chemical-genetic interaction map (Martins et al., Cancer Discov, 2015).

The phase I dose-escalation study of five-day intermittent oral lapatinib therapy in patients with human EGFR2-overexpressing breast cancer by Drs. Jo Chien, Pamela Munster, Michelle Melisko, Hope Rugo, John Park, Andrei Goga, and Mark Moasser is an excellent example of the intercollaborative work within the Breast Oncology Program (Chien et al., J Clin Oncol, 2014). Several agents in the pipeline for I-SPY 2 are now being tested by these investigators for safety in combination with taxanes, the backbone of I-SPY 2.

Dr. Rugo was the lead author of the important Bolero-2 trial evaluating the incidence and time-course of everolimus-related adverse events (AEs) in postmenopausal women with hormone-receptor-positive advanced breast cancer, which had shown significant clinical benefit when administered with exemestane (Rugo et al., Ann Oncol, 2014). The observed AEs occurred soon after initiation of therapy, were typically of mild or moderate severity, and generally manageable with dose reduction and interruption. Similarly, the therapeutic benefits and side effects of local radiotherapy were evaluated by Drs. Cathy Park and Barbara Fowble (Sethi et al., Lancet, 2014).

Drs. Cheryl Ewing and Esserman contributed to the knowledge of operation techniques, comparing total skin-sparing mastectomy and immediate breast reconstruction in an evolution of technique and assessment of outcomes (Wang et al., Ann Surg Oncol, 2014). Drs. Rugo and van ‘t Veer participated in the first international harmonization effort to reach consensus for advanced breast cancer treatment, which published its second statement in 2014, ABC2 (Cardoso et al., Ann Oncol, 2014).

Theme 5: Outreach, Clinical Care Delivery, and Outcomes

Dr. Jeffrey Belkora started the successful and much appreciated program of patient navigation in the breast care clinic with pre-medical interns. Dr. Nancy Burke described the improvement of healthcare empowerment through breast cancer patient navigation by a mixed methods evaluation in a safety-net setting (Gabitova et al., BMC Health Serv Res, 2014).

Preference-, psychosocial symptom-, and anxiety-exploring questionnaires, directly connected with pending referrals to the appropriate services, are administered to all patients visiting the breast care clinic. Recently, Drs. Melisko, Esserman, and Rugo added a web-based module for survivorship symptom management after breast cancer treatment to this system. They described the success of this web-based approach enabling efficient patient centered information exchange in a randomized controlled trial (Kaplan et al., Cancer Epidemiol Biomarkers Prev, 2014).

Drs. Kaplan, Kerlikowske, Leah Karliner, and Eliseo Perez-Stable (Cancer Control Program) are focused on breast cancer care outreach among the underserved. They conducted a randomized, controlled trial to establish increased discussion of breast cancer at the point of patient contact in primary care (Wheelock et al., Cancer, 2014).