The primary objective of the Fifth Annual Symposium on Personalized Therapies and Best Clinical Practices for Breast Cancer and its corresponding enduring materials is to help you develop subsequent improvements in your practice so that you can treat your patients with the optimal personalized approaches in order to improve patient outcomes and minimize drug-induced toxicities.

This symposium is "case-based" learning. The symposium format extensively utilizes adult learning principles. The learning design is one that is very highly interactive between the learners and the faculty. Each didactic presentation begins with a patient case study and the faculty uses the Audience Response System (ARS) for engaging you, the learner, at the outset of each segment of the program. This approach has been so successful that it is used for all of our live symposia to further facilitate adult learning. In addition, each of the symposium’s sessions will include one additional, dedicated, interactive clinical case studies session involving you and the faculty with ARS. Each symposium session will include a Roundtable Faculty Panel Discussion so that you can be prepared to apply the data presented and reviewed to improve your practice. And each symposium session will conclude with a Q & A period for additional involvement with the faculty.

According to the American Cancer Society 2011 Cancer Facts and Figures there were an estimated 232,620 new breast cancer patients with 39,970 deaths attributed to this malignancy in the United States in 2011. Thus, adequate improvement of outcomes in breast cancer patients remains an unmet need and a Practice Gap for oncologists.

MOLECULAR TESTS AND CLASSIFICATIONS FOR PERSONALIZING BREAST CANCER PATIENT THERAPIES
Currently, there exists a robust and complex molecular classification system for breast cancer based upon hormone receptor status, HER2 status and gene-based expression profiling, assays and signatures, circulating tumor cells, and other molecular testing using several biomarkers, resulting in an increasingly large number of testing options and recommendations.

The heterogeneity of breast cancer can be used to help physicians plan treatment options for improving outcomes in their patients using a personalized approach to therapy. Gene expression profiles are being used more frequently to distinguish among several subclasses of breast cancers on the basis of their biology and cell origin. BRCA status is used as both a prognostic and predictive molecular marker for some patients and systemic therapies, especially patients with triple-negative breast cancer. Gene profiling, other gene-based tests and several HER2-based molecular biomarker tests, including FISH, IHC and the INFORM Dual ISH test, as well as tests for circulating tumor cells are continuing to help clinicians personalize therapies for their patients with breast cancer for improving patient outcomes of this malignancy. The lack of widespread knowledge and understanding of the most current oncology practice guidelines and available tests for breast cancer prognosis and prediction of effective therapy is a Practice Gap for community-based oncologists.

IMPROVING OUTCOMES IN PATIENTS WITH HER2-POSITIVE BREAST CANCER
It is well established that HER2 is amplified in 25 to 30 percent of breast cancers; and its presence marks an aggressive form of the malignancy, historically associated with significantly shortened disease-free and overall survival in the pre-trastuzumab era more than a decade ago. HER2 is one of the most important cellular targets that have lead to the development of personalized therapies for breast cancer. HER2 status is also an essential and well documented determinant of who should receive anti-HER2 therapy. Patients with HER2-positive breast cancer are treated in the adjuvant, neoadjuvant and metastatic settings with a variety of current and emerging novel strategies targeting HER2. Strategies for these patients are in clinical development that target or inhibit other biologic pathways.

IMPROVING OUTCOMES IN PATIENTS WITH ER-POSITIVE BREAST CANCER
Approximately 65 percent of breast cancers express the estrogen receptor (ER) that is subject to growth stimulation by the circulatory estrogens. Because estrogen plays a key role in the growth and proliferation of cancer cells in these patients, endocrine therapy is a standard treatment for hormone receptor-positive breast cancer patients. Traditionally, the hormonal therapy used was a first-generation, selective estrogen receptor modulator (SERM) tamoxifen, which had shown reductions in disease recurrence and mortality. However, tamoxifen is associated with an increase in the risk of endometrial cancer and thromboembolic events and thus, the need for drug therapies with less toxicity and improved efficacy exists. The next generation of hormonal drug therapies, aromatase inhibitors (AIs), improved the treatment of hormone receptor-positive breast cancer in post-menopausal women. Large clinical trials that evaluated the use of AIs as adjuvant treatment in post-menopausal women with hormone receptor-positive breast cancer revealed that increased efficacy was observed with AI treatment when compared with tamoxifen.

One of the most challenging aspects of using endocrine therapy is personalizing therapy---determining which patient should receive which agent and determining how long should endocrine therapy be used in a specific patient. Gene expression profile assays may help physicians personalize treatment for their patients. The use of molecular biomarkers, predictive factors and gene expression profiles assays in a personalized approach to breast cancer treatment is an existing physician Practice Gap.

At ASCO June 2011, data was presented by Dr. Jose Baselga on the phase III BOLERO-2 trial in which everolimus is being used in combination with exemestane for the treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer who are refractory to letrozole or anastrozole. BOLERO-2 is a multinational, double-blind, placebo-controlled phase III study in postmenopausal women with ER-positive, locally advanced or metastatic breast cancer whose disease was refractory to aromatase inhibition and documented recurrence or progression were stratified by sensitivity to prior hormonal therapy and the presence of visceral metastasis and then randomized (2:1) to everolimus (10 mg daily) or matching placebo orally once daily, with both arms receiving exemestane (25 mg daily). Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was PFS as assessed by the investigators. Secondary outcomes included OS, ORR, time to deterioration of ECOG performance status, safety, and change in quality of life scores over time. Between June 2009 and January 2011, 723 patients were randomized from 24 countries; 84 percent had hormone sensitive-disease and 56 percent had visceral disease. This trial is ongoing. No further data was provided in the published June 2011 ASCO abstract. However, an important update is as follows. In a press release by Novartis on July 5, 2011, and from data presented at the ECCO-ESMO meeting in Stockholm in September 2011, by Dr. Jose Baselga, combining everolimus with exemestane appears to lengthen disease-free survival in postmenopausal women with advanced breast cancer who have failed other hormone therapy. This two-drug combination was associated with a significant 57 percent reduced relative risk of disease progression for patients with estrogen receptor (ER)-positive, HER2-negative disease. It was announced at ECCO-ESMO that the trial was stopped early after the February 2011 interim analysis found a significantly better progression-free survival by local assessment for the combined therapy group: median 6.9 months versus 2.8 months.

IMPROVING OUTCOMES IN PATIENTS WITH TRIPLE-NEGATIVE AND HER2-NEGATIVE BREAST CANCER
The ER/PR-negative, HER2-negative phenotype of breast cancer, triple-negative breast cancer, (TNBC) represents approximately 15 percent of all newly diagnosed breast cancers and conforms a uniformly poor prognosis with an increased incidence of distant-recurrence as well as death compared to other breast cancers. The triple-negative phenotype essentially results in lack of clinical utility of traditional biomarker-driven advances such as the use of hormonal therapy or HER2-directed therapies. When a phenotype is defined by the lack of biomarker expression, there is a large risk for misidentification. False identification of negativity for receptor is possible due to laboratory errors.

Despite an overall increase in knowledge of the biology and natural history of TNBC, no standard treatment algorithm or guideline exists to educate on evidence-based management of this disease. As such, learning opportunities focused on the clinical management of metastatic or early stage TNBC must identify the incorporation of existing therapeutics, when feasible, and also prepare the oncology community with the scientific rationale for future advances that exploit new biologic understanding. In the coming months to years, it is anticipated that rational and targeted therapy will become a reality for TNBC. A large number of TNBC trials are ongoing in both the adjuvant as well as metastatic setting, and they may likely change the paradigm of standard treatment by use of personalized therapies.

IMPROVING BREAST CANCER PATIENT OUTCOMES WITH OTHER NOVEL STRATEGIES
Because of the classification of agents, several systemic therapies are addressed both here and also in previous sections of this Needs Assessment/Practice Gap analysis/identification including HER2-postive breast cancer, triple-negative breast cancer and other breast cancer subtypes. Thus, it is difficult to classify the vast number of therapeutic options for helping improve outcomes of breast cancer patients because many of the therapeutic strategies and agents are active in more than one subtype of breast cancer. Several important novel agents and strategies, including agents already marketed with different FDA indications, as well as investigational therapies under clinical evaluation for breast cancer patients are reviewed here.

Some of the novel strategies and agents worthy of further review include the taxane: nab paclitaxel, the microtubule dynamics inhibitor: eribulin, the epothilone: ixabepilone, the mTOR inhibitors: everolimus and ridaforolimus, the HDAC inhibitors: vorinostat, entinostat and panobinostat, the novel irreversible EGFR/HER2 tyrosine kinase inhibitor, afatinib, the multi-kinase inhibitors: sorafenib and dasatinib and bortezomib, ramucirumab, liposomal doxorubicin, MM-121, NKTR-102, HER2/GM-CSF vaccine, and tanespimycin (heat shock protein 90). These agents and combinations of them are either FDA-approved for breast cancer or agents who have also demonstrated activity in breast cancer patients with advanced and metastatic disease in clinical trials, most of which are ongoing. A Practice Gap exists in the community-practice setting because many community oncologists are not sufficiently aware of the opportunities to enroll selected breast cancer patients in these trials to receive investigational therapy with these novel agents.

TARGETING THE BONE MICROENVIRONMENT
The bone is the most common site of distant metastases in breast cancer patients. The economic burden of U.S. patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience a Skeletal Related Event (SRE) incur significantly higher medical costs compared with those who do not experience an SRE.