Canadian initiatives for locally advanced breast cancer research and treatment : inaugural meeting of the Canadian Consortium for LABC

s?&vmview=abst_detail_view&confID=65&abstract ID=34689; cited April 25, 2011] 4. Smith JW, Buyse M, Rastogi P, et al. Epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab and bevacizumab as neoadjuvant therapy for her2-positive locally advanced breast cancer (labc) or as adjuvant therapy for her2positive pathologic stage iii breast cancer (PS3BC): a phase ii trial of the nsabp Foundation Research Group [abstract 580]. J Clin Oncol 2009;27:. [Available online at: www.asco.org/ ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view& confID=65&abstractID=34849; cited April 25, 2011] 5. National Surgical Adjuvant Breast and Bowel Project (nsabp). NSABP Protocol Chart March 2011. Pittsburgh, PA; nsabp; 2011. [Available online at: www.nsabp.pitt.edu/ nsabp_Protocol_Chart.pdf; cited April 28, 2011] 6. Trudeau ME, Eisenhauer EA, Higgins BP, et al. Docetaxel in patients with metastatic breast cancer: a phase ii study of the National Cancer Institute of Canada–Clinical Trials Group. J Clin Oncol 1996;14:422–8. 7. Parissenti AM, Chapman JA, kahn HJ, et al. Association of low tumor rna integrity with response to chemotherapy in breast cancer patients. Breast Cancer Res Treat 2010;119:347–56. 8. Liedtke C, Mazouni C, Hess kR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275–81. 9. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005; 11:5678–85. 10. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329–34. 11. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 2010;119:551–8. 12. Wang S, Yang H, Tong F, et al. Response to neoadjuvant therapy and disease free survival in patients with triple-negative breast cancer. Gan To Kagaku Ryoho 2009;36:255–8. 13. Stephens PJ, McBride DJ, Lin ML, et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009;462:1005–10. 14. Shah SP, Morin RD, khattra J, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 2009;461:809–13. Correspondence to: Muriel Brackstone, London Regional Cancer Program, Division of General Surgery/Surgical Oncology, 790 Commissioners Road E, Room A3-931, London, Ontario N6A 4L6. E-mail: Muriel.Brackstone@lhsc.on.ca * London Health Sciences Center, London, ON. † University of Montreal, Montreal, QC. ‡ BC Cancer Agency, Vancouver, BC. § Cross Cancer Institute, University of Alberta, Edmonton, AB. || Sunnybrook Odette Cancer Centre, Toronto, ON. # The Ottawa Hospital Cancer Centre and the University of Ottawa, Ottawa, ON.


INTRODUCTION
Driven by the advent of molecular profiling and the development of novel targeted therapies, the landscape of breast cancer research and treatment is changing rapidly.This situation is particularly true in the setting of locally advanced breast cancer (labc), which provides a unique platform for testing the efficacy of new therapies and a forum for correlative tissue studies, allowing for an increased understanding of the effects of these therapies in vivo.The hope is that this preoperative model will allow for more rapid development of new treatments and individualized treatment strategies.This new direction has resulted in unique opportunities for clinical and scientific collaboration.The Canadian Consortium for LABC (colab) is a multi-disciplinary Current OnCOlOgy-VOlume 18, number 3 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).approaches to treatment have been based on a "one size fits all" assumption, without an in-depth understanding of the biology and diversity of the disease.Recently, a more tailored approach to therapy has revolutionized thinking about breast cancer research and treatment.The goal of this new approach, often called the "bench to bedside" approach, is to develop more effective and less toxic therapies through the clinical translation of biologically relevant molecular information.The development of trastuzumab (Herceptin: Genentech, San Francisco, CA, U.S.A.), a monoclonal antibody directed at the human epidermal growth factor receptor 2 (her2) oncoprotein, marks a major success of this approach to therapy.
The clinical translational approach begins with target identification through molecular analysis of tumour specimens and comparison with histopathologic features and disease outcomes.The next step is molecular target validation, which involves preclinical confirmation in vivo using cell lines and animal models and development of agents that modulate expression or function of the target molecule.In clinical trials, validated methods of target modulation are applied to human disease-the context in which the molecular target was originally identified.Subsequent trials then develop and refine the use of targeted agents by varying the dosing, schedules, and combinations with other treatment agents.
Further clinical translational research promises to improve existing therapies as more pathway alterations are recognized in primary tumours and new targets are identified and validated.Large adjuvant studies such as beth (NCT00625898 at clinicaltrials.gov/ct2/search) and altto (NCT00490139 and NCT00553358 at clinicaltrials.gov/ct2/search)focus on the clinical validation of molecular concepts and offer particular promise for advancing early breast cancer treatment.The key challenges of translational research are the definition and identification of patient subpopulations that are eligible for molecularly-directed therapy and the optimal use of such agents in combination with standard therapies.

Plenary Lecture -NSABP: Historical
Perspective and Future Directions for LABC The National Surgical Adjuvant Breast and Bowel Project (nsabp) has been integral in defining the treatment landscape of labc.That group's trials, among others, have established the equivalence of neoadjuvant and adjuvant therapy, defined chemotherapy standards (for example, B-18, B-27) 1 , and identified the biomarkers predicting outcomes of targeted therapy (for example, FB-AX-003) 2 .The nsabp has made important advances in incorporating targeted therapy such as bevacizumab (for example, FB-4 and FB-5) 3,4 , and ongoing trials continue to explore emerging strategies such as integration of the oral irreversible pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib and use of the dual her2 receptor and epidermal growth factor receptor tyrosine kinase inhibitors neratinib (HkI-272) and lapatinib [for example, FB-6, FB-7, and B-41 respectively (NCT00849472, NCT01008150, and NCT00486668 at clinicaltrials.gov/ct2/search)].
The poly-adenosine diphosphate ribose polymerase inhibitor BSI-201 will also be tested in labc treatment regimens (B-48) 5 .This body of research reminds us that labc is a heterogeneous disease comprising a mixture of slow-and rapidly-growing tumours.Past approaches to preoperative therapy were unselective and based on clinical signs and symptoms.It is now clear that preoperative therapy presents unique opportunities to quickly evaluate new treatments.The ability to monitor response to therapy based on measurable changes in tumour size and on biomarkers of response evident in molecular analyses of tumour samples and the ability to use pathologic complete response (pcr) as a predictor of survival outcomes make this setting well-suited for a rapid assessment of emerging targeted agents.Strategies for future labc research should include organization of clinics to maximize trial accrual, initiation of trials that enrol patients with high-risk disease (selected by biologic markers) and with postsurgical residual disease, and investigation of specific targets to improve pcr rates.

Plenary Lecture -Reduction in Tumour RNA Integrity Is Associated with Clinical Response to Neoadjuvant Epirubicin/Docetaxel Chemotherapy in Breast Cancer Patients
Presenter: Amadeo M. Parissenti, Sudbury Regional Hospital, Sudbury, Ontario Treatment of certain subtypes of labc, such as inflammatory disease, can be problematic.Low rates of clinical complete response and pcr in these patients suggest that most patients will experience disease progression.The ability to monitor response to chemotherapy would be highly beneficial, because lack of response could be detected early and alternative treatments such as surgery, radiation therapy, or others may then be used.Currently, quantification of rna integrity as a biomarker of response to chemotherapy is under development.Reduced rna integrity is associated with cell death, and in the context of chemotherapy, cell death indicates a positive response to treatment.In the ncic Clinical Trials Group (ctg) ma.22 trial of docetaxel plus dose-dense epirubicin in labc patients 6 , the correlation between mid-treatment maximum tumour rna integrity number (rin) and drug dose level suggests that rin is a clear biomarker Current OnCOlOgy-VOlume 18, number 3 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
of treatment response 7 .Also, although traditional pathology analyses of tumour cellularity at midtreatment are unable to predict a post-treatment pcr and although other methods for predicting chemotherapy response (for example, fluorodeoxyglucose positron-emission tomography scans) are limited, current data suggest that mid-treatment maximum tumour rin is predictive of post-treatment pcr 7 .Furthermore, serial oligonucleotide microarrays of samples from patients with threshold rin values would allow for an analysis of gene cluster expression to identify gene signatures predictive of response to treatment.Further studies are ongoing.

Plenary Lecture -Neoadjuvant Systemic Therapy: A Surgeon's Revolution
Presenter: Jean-Francois Boileau, Sunnybrook Odette Cancer Centre, Toronto, Ontario The nature of neoadjuvant therapy affords unique opportunities for innovative approaches to breast cancer research and treatment.The systemic administration of neoadjuvant therapy allows for improved breast conservation and in vivo tumour response as a biological model for clinical trials and drug development.
Because neoadjuvant therapy precedes surgery, the advancement of labc research rests in large part with surgeons.Surgeons play a pivotal role in clinical trial accrual and neoadjuvant treatment selection.They are experts in the management of patients selected for neoadjuvant systemic therapy: They order the molecular analyses (for example, estrogen and progesterone receptors, her2) on the diagnostic core biopsies to guide subsequent treatment, and they often have to arrange for the clipping of lesions and marking of the tumour site to plan for breastconserving surgery after neoadjuvant therapy.Additionally, surgeons act as research scientists because they can procure core biopsy and surgical samples and are skilled at measuring response to treatment by clinical examination.
The National Comprehensive Cancer Network guidelines indicate that the best management of any cancer patient occurs in a clinical trial.Establishing neoadjuvant chemotherapy as a standard of care for certain subtypes and stages of breast cancer-and favouring delivery of treatment as part of a clinical trial-was the impetus for a new model of patient care formulated at the Sunnybrook Odette Cancer Centre in Toronto, Ontario.In this model, surgeons and medical oncologists run concurrent clinics, allowing them to quickly identify patients who are eligible for neoadjuvant trials and to discuss enrolment with those patients.The clinical trial-based model improves efficiency by facilitating patient accrual and provides the highest quality patientcentred care.

Plenary Lecture -Neoadjuvant Therapy for
Triple-Negative LABC Presenter: Rebecca Dent, Sunnybrook Odette Cancer Centre, Toronto, Ontario Triple-negative disease is a subset of breast cancer with a unique biologic signature and pattern of disease progression 8 .It represents approximately 15% of all breast cancers and consists of patients with tumours that are estrogen and progesterone receptor-negative and also her2-negative by immunohistochemistry (1+) or fluorescence in situ hybridization, or both.Basal-like breast cancer is another subgroup with a particularly poor prognosis; it also overlaps the triple-negative subgroup.Identification of basal-like disease is often difficult, because a definitive diagnosis requires microarray analysis of an expanded panel of marker genes.Thus, immunohistochemical assays indicating triple-negative status are often used as surrogate markers for basal-like breast cancer, and yet not all triple-negative disease is basal-like.
Retrospective reviews and subgroup analysis of prospective neoadjuvant chemotherapy trials have both provided important insights into the biology and chemosensitivity of triple-negative breast cancer (tnbc) compared with other subtypes.Those studies have consistently reported increased objective response rates and pcrs in tnbc compared with non-tnbc [8][9][10][11] .
Although patients with tnbc have an overall increased risk of relapse and death, patients who do achieve a pcr with neoadjuvant treatment have a favourable prognosis that is not statistically different from that in patients with non-tnbc 8,10,12 .Evidence suggests that anthracycline-taxane combinations and dose-dense or metronomic schedules may be particularly effective in this patient group.One of the largest studies to evaluate response to neoadjuvant therapy in tnbc compared with non-tnbc included 1118 patients treated between 1985 and 2004 at the MD Anderson Cancer Center 8 .Patients with tnbc who achieved a pcr had 3-year overall survival rates similar to those in the non-tnbc group (94% and 98% respectively, p = 0.24), but patients with tnbc who had residual disease after neoadjuvant therapy had a worse 3-year overall survival (68% vs. 88%, p = 0.0001).Although there is no direct evidence to recommend the routine use of neoadjuvant therapy over adjuvant therapy, the neoadjuvant approach provides an opportunity to determine in vivo tumour response to chemotherapy and remains an attractive option for the treatment of tnbc.In an era of targeted treatment strategies, the need to understand the biology of tumour response to targeted drug exposure is increased.Phase 0 and window-ofopportunity (wo) studies likely have little or no immediate benefit for the patient, and yet their results may accelerate the pace of molecular target identification and bench-to-bedside clinical translation.A phase 0 clinical trial is a first-in-human proofof-concept study that evaluates target modulation and the biologically effective dose of a new therapeutic agent, including both pharmacodynamic and pharmacokinetic analyses.The phase 0 trial is not designed to provide therapeutic benefit to patients.Unlike traditional dose-escalation phase i trials, only non-toxic drug doses are administered for a short period of time to a limited number of patients with incurable disease.By contrast, preoperative wo studies involve patients with primary operable breast cancer and target a particular period during the wait for surgery to expose systemic treatment-naïve tumours to targeted agents.The wo studies involve a curable patient population, and therefore more safety and toxicity data on the new therapeutic agents are needed before such studies can be initiated.The ability to assess changes in molecular pathways and signalling before and after exposure to new targeted agents can provide critical insights into the level of specificity of those agents and can aid in the design of future clinical trials.

Plenary
The future of breast cancer research is likely the more frequent use of combinations of targeted agents with conventional therapies.In Canada, expert investigational teams are motivated to carry out such research initiatives.However, the challenges that remain are to establish the necessary funding and infrastructure (for example, those for imaging, biopsies, tissue acquisition, molecular analysis), to attract the interest of the developers of novel targeted agents, and to ensure timely initiation and completion of wo trials.

Plenary Lecture -Creation of Pan-Canadian Standard Operating Procedures for Patients Receiving Preoperative Therapy for Locally Advanced Breast Cancer
Presenters: Nathaniel Bouganim and Mark Clemons, Ottawa Regional Cancer Centre and University of Ottawa, Ottawa, Ontario Interest in the use of neoadjuvant therapy in the treatment of labc is increasing, and greater national collaboration will advance knowledge of labc and improve treatment outcomes.Those goals will be achieved by increasing the number of available clinical trials, increasing patient accrual, and enabling greater access to existing tissue and data banks.Improved access to those resources will promote identification of new biologic targets, expedite the development of novel therapeutics, and result in ever-improving treatment strategies.
A particularly important aspect of collaborative clinical research efforts is trial design.Trial design can be enhanced by working with established Canadian and international partners from academia and industry (nsabp, Neo-Big, I-SPY2) who bring significant expertise and experience in trial design and implementation.There is also a need for the development of pan-Canadian standard operating procedures to guide existing collaborative efforts and to standardize the way in which new collaborations are planned and accomplished.
Standardized guidelines for the collection of samples during surgery will promote tissue banking of labc samples and ensure uniformity of tissue and patient data collection between provinces, thereby improving quality control in the collection and handling of data during trials.Ultimately, design and implementation of standard operating procedures to guide Canadian labc research in the context of neoadjuvant treatment will provide a wealth of linked clinical data and tissue to researchers while respecting ethical requirements.

Plenary Lecture -Building Successful Clinical
Trials for LABC Presenter: John Mackey, Cross Cancer Institute, University of Alberta, Edmonton, Alberta The biologic diversity of breast cancer is staggering 13,14 , and the application of drugs to unselected patient populations without a specific molecular rationale is unlikely to yield useful results.It is therefore critical to target treatment to specific patient populations defined by the biology of the disease.Cell lines represent a powerful tool through which the molecular subtypes of common cancers can be represented.The process begins with large panels of cultured breast cancer cells that are characterized by whole-genome expression analysis, comparative genomic hybridization, and dna sequencing for mutations in key proto-oncogenes and tumour suppressor genes.These cells are then used in highthroughput screening to study drug sensitivity, to identify mechanisms of action for novel agents, and to determine the potential for synergistic activity in combination with other agents.The molecular profiles of drug-sensitive lines are then applied to the breast cancer population to select the patients most likely to respond to clinical trial therapies.
The chances of success in clinical trials can be greatly improved by planning biology-based trials for molecularly and geographically targeted labc populations.Trials designed to evaluate efficacy in a subset of patients with a specific set of molecular markers cannot readily be accrued solely within Current OnCOlOgy-VOlume 18, number 3 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
Canada, which means an increased need for partnerships and a global research perspective.To address those challenges, translational research groups such as Translational Research in Oncology are expanding to South America (Uruguay office) and Mexico with financial assistance from private donors.Basing labc trials in developing countries with a very high prevalence of labc improves the local breast cancer care, speeds trial accrual, and augments the research needed to improve breast cancer treatment globally.

SUMMARY
The ever-changing landscape of breast cancer research and treatment is driving a greater interest in, and focus on, the benefits of treating patients in the neoadjuvant setting.The merits of neoadjuvant therapy include the ability to observe tumour response during treatment, the capacity to collect tumour samples, and the ability to characterize molecular response to treatment.The shift to a biology-driven approach and the accelerating pace of translational research highlights the need for increased collaboration across disciplines and throughout the country.This year's colab meeting discussed the current state of clinical and translational research in Canada and established a functional definition of labc as stages iib and iii disease.It is clear that exciting Canadian initiatives in labc research are underway, focusing on identifying molecular signatures to allow development of new tailored therapies, on subtyping the patient populations that are most likely to respond to targeted agents, and on developing methods to measure response to treatment in labc patients.The creation of patient subgroups presents a challenge for patient accrual, which is being addressed by global expansion of clinical trials.The sharing of clinical samples and data to identify patients eligible for trial enrolment and the establishment of funding partnerships are becoming even more critical.Initiatives to foster and improve collaboration are imperative to ensure ongoing progress in labc research and treatment.Priorities include forming a strong national research infrastructure that supports multidisciplinary national collaboration, establishing partnerships to design and run clinical trials, and creating a nationally linked Web-based platform to facilitate the sharing of clinical data and research materials.
The colab is dedicated to ongoing progress in labc research.Initiatives to increase collaboration continue, as demonstrated by the publication of this manuscript and the organization of the most recent colab meeting, which was held at Langdon Hall, Cambridge, Ontario, May 1-2, 2011, and was chaired by Dr. Jean-Francois Boileau.We thank all who attended the inaugural meeting in 2010 and all who helped to make that meeting a

Lecture -Phase 0 and Window-of- Opportunity Studies in Primary Operable Breast Cancer: Are We Ready? Presenter
: Stephen Chia, BC Cancer Agency, Vancouver, British Columbia Current OnCOlOgy-VOlume 18, number 3 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).