32 ND ANNUAL December 9th-13th, 2009 AN UPDATE OF KEY PRESENTATIONS

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1 DECEMBER 9TH-13TH, 2009 SAN ANTONIO BREAST CANCER SYMPOSIUM 32 ND ANNUAL December 9th-13th, 2009 AN UPDATE OF KEY PRESENTATIONS Sona Gandhi, MD, FRCPC Suni Verma, MD, MEd, FRCPC Sunnybrook Odette Cancer Centre, Toronto, CANADA I. BREAST CANCER EPIDEMIOLOGY Lifestye Factors and Breast Cancer Risk Breast Cancer Prevention A Goba and Historica Perspective (Penary Session) V Bear, University of Oxford. In the 18th and 19th centuries, breast cancer was thought to be an occupationa disease of nuns (Coaborative Group on Human Factors in Breast Cancer. Lancet ) The incidence was 2.7% versus 0.4% in the genera popuation; mortaity was aso 7 times higher (Rigona-Stern, 1842) and this was thought to be ref ective of chidbearing practices. Incidence of breast cancer in deveoped countries: 6.1% vs. 1% in rura Asia and Africa (WHO/IARC 2002). If deveoped nations had simiar chidbearing and breastfeeding practices, breast cancer incidence estimated to be haved to 3%. As chidbearing practices are impractica to target, coud focus on deveoping interventions (such as an adut vaccine or hormona therapies) to mimic the hormona changes of pregnancy/actation. Controversia. Other risk factors for breast cancer in deveoped nations are earier age of menarche, increased height and BMI, and increased acoho consumption. These factors are independent of poygenetic risk modeing. Impact of Chidbearing 6.1% breast cancer incidence in deveoped countries. Larger famiy size Longer breastfeeding Estimated 2.7% breast cancer incidence in deveoped countries if had arger famiy sizes and onger duration of breast feeding. Coaborative Group on Hormona Factors in Breast Cancer, Lancet Acoho Consumption and Breast Cancer Prognosis and Surviva in the LACE Study A Prospective Cohort of Breast Cancer Survivors. ML Kwan, Caifornia. Increased acoho (>6g/day, or 0.5 drinks/day or 3-4 drinks/week) independenty increases breast cancer recurrence risk, HR 1.34 (p=0.05). Adjusted for age at diagnosis, BMI, disease stage, hormone receptor and ymph node status, tamoxifen use, and overa treatment status. Association highest in postmenopausa and obese women. >6g/day of acoho increases risk of breast cancer death HR of 1.51 (p=0.05). Tota mortaity in this cohort NOT affected by acoho; ikey offset by protective effect of moderate acoho use on cardiovascuar heath. 1

2 SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 9TH-13TH, 2009 Effect of Obesity on Prognosis after Eary Breast Cancer M Ewertz, Denmark, on behaf of Danish Breast Cancer Cooperative Group Study aim: to determine if obesity is an independent risk factor for breast cancer recurrence or death, or for poorer response to adjuvant treatment. Adjusting for other prognostic variabes, patients with BMI >25 had a statisticay signifi cant 42-46% increase in deveoping distant metastases within 10 years, and 26-38% risk of dying from breast cancer 10 or more years after diagnosis. EPIDEMIOLOGY TAKE HOME MESSAGE Breast cancer risk is increased by ifestye patterns in deveoped countries (such as ower rates of chidbearing, increased acoho consumption, and obesity.) Adoption of simiar ifestye habits in deveoping countries is eading to a rising breast cancer incidence in these areas. Need to deveop nove strategies to decrease the incidence of breast cancer. Breast cancer prognosis and mortaity independenty affected by acoho and obesity. In addition to standard breast cancer treatment, we shoud reguary advocate ifestye changes in patients, incuding decreased acoho consumption, weight oss, and exercise. II. BREAST TUMOUR BIOLOGY Therapeutic Impications of the Moecuar Portraits of Breast Cancer CM Perou, North Caroina. Reviewed the heterogeneity of breast tumours based on moecuar bioogy and histopathoogy. Breast cancer prognosis is impacted greaty by these subtypes. Sorie T et a, PNAS.2001 HER-2 IN BREAST CANCER Approximatey 20% of breast carcinomas are cinicay HER-2 positive (by standard histopathoogic techniques.) Introduced new concept of HER-2 over-expression: HER-2 enriched at moecuar eve. Represents 10-15% of a breast tumours. Not a are cinicay HER-2 positive (exampe: tripe negative). Conversey, 1/2 to 2/3 of a cinicay HER-2 positive tumours are aso HER-2 enriched. The rest are Lumina B, Lumina A, and Basa-ike. Baseine prognosis is sti poor. Trastuzumab and chemotherapy benefi t remains high in cinicay Her-2 positive patients, and remains to be studied in the moecuar Her-2 enriched subtype. TRIPLE NEGATIVE (TN) BREAST CANCER Understanding of this tumour subtype continues to deveop. 75% of TN tumours are truy basa-ike. Basa-ike tumours represent 10-15% of breast tumours overa. 75% of basa ike tumours are aso TN. Show distinct ce of origin or deveopmenta stage of arrest. More than 50% have p53 mutations. Highy proiferative, highy aneupoid, and associated with BRCA-1 mutations. Baseine prognosis poor, high chemotherapy benefi t,?parp-inhibitor benefi t. The TN cassifi cation misses 25% of true basa ike tumours and incudes 25% of tumours that are NOT basa-ike. New subtype introduced: Caudin-ow. 5-10% of tumours, typicay TN, ow expression of ce junction proteins, ymphocytic infi trates, and predominanty stem ce features. 2

3 DECEMBER 9TH-13TH, 2009 SAN ANTONIO BREAST CANCER SYMPOSIUM TUMOUR BIOLOGY TAKE HOME MESSAGE Each breast tumour bioogic subtype corresponds with ce cyce arrest at a unique phase of mammary deveopment. The earier the arrest stage, the more tripe negative and/or basa ike features the tumour is ikey to have. Latter stages of arrest are ikey to create tumours with more differentiated, umina features. Our understanding of tumour bioogy and its impications on tumour behaviour, prognosis, and therapeutic impications continues to grow. Moecuar and histopathoogic features of tumours need to be considered in concert. Prat, Perou et a. Nat Med III. ENDOCRINE THERAPY Five Years of Exemestane as Initia Therapy Compared to Tamoxifen Foowed by Exemestane for Five Years The TEAM Tria. A prospective, randomized, phase III tria in post-menopausa women with hormone-sensitive eary breast cancer. D Rea, University of Birmingham, United Kingdom, on behaf of TEAM coaboration. Exemestane versus tamoxifen sequenced to Exemestane at 2-3 years. Resuts of panned anaysis: Median foow up 5.1 years. 60% of patients competed 5 year foow up. Largest AI study to date, comparing two of most common treatment strategies. A patients were HR+, and baseine characteristics were we-baanced. No difference in T E versus E upfront in DFS or OS in ITT popuation. Noda status did not inf uence outcome. There were more DVTs with tamoxifen, and more osteoporosis and fractures with exemestane. Significant discontinuation rate which may have impacted resuts: 29% of patients discontinued tamoxifen and 18.9% discontinued exemestane in the fi rst 2.75 years. It is uncear what happened to these patients, and fi na pubication wi need to be reviewed. 5 years may be too short a foow up period, particuary for ymph node negative patients. 3

4 SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 9TH-13TH, 2009 Disease Reated Outcome with Long Term Foow up An updated anaysis of the Intergroup Exemestane Study (IES) JM Biss, United Kingdom, on behaf of IES Steering Committee. Compared tamoxifen for 5 years versus tamoxifen for 2-3 years with switch to exemestane to compete 5 years. Median foow up 91 months. 85% HR +, haf were ymph node +. Improvement in OS with T E: absoute difference at 5 years 1.4%. Absoute difference at 8 years 2.4 % HR 0.85 p=0.04. Confirmed that risk of recurrence persists beyond 5 years. Other findings: decreased bone ony metastases in exemestane group (75 events versus 109 with tamoxifen), no difference in viscera metastases. Aso ess non-endometria secondary cancers were found with exemestane. This is unexpained, and shoud be studied in a metaanaysis of AI trias. ENDOCRINE TREATMENT TAKE HOME MESSAGE It is important to integrate AI therapy in the treatment of post-menopausa HR +ve breast cancer. Benefi t is modest and different strategies may have minima differences in outcome. There is a persistent risk of disease reapse beyond fi ve years, despite integrating tamoxifen and AI therapy. In addition, we need to better understand what type of distant events are prevented by each strategy. Adherence to endocrine therapy continues to be a great concern; we need to better understand and address patient adherence issues. IV. CHEMOTHERAPY PACS 01 Updated Anaysis B Coudert, France, on behaf of FNCLCC Compared FEC-100 chemotherapy (5FU 500mg/m2, epirubicin 100mg/ m2, cycophosphamide 500mg/m2, a on day 1) every 21 days x 6 cyces, to FEC-100 for 3 cyces, foowed by docetaxe (100mg/m2) every 21 days x 3 cyces (FEC-D). Updated 8 year anaysis. At 5 year anaysis, DFS and OS were improved with FEC-D (DFS-78.3% vs. 73.5%, OS-90.7% vs. 88.7%). At 8 years, continued benefit with FEC-D: DFS FEC-D: 70.2% OS FEC-D: 83.2% FEC: 65.8% FEC: 78% (HR 0.85 p=0.035) (HR 0.79 p=0.024) CHEMOTHERAPY TAKE HOME MESSAGE The DFS and OS benefi t of a widey used adjuvant chemotherapy regimen incorporating anthracycines and taxanes (FEC100-Docetaxe), remains after 8 years of foow up. The absoute OS benefi t is even greater at 8 years (cose to 5%). 4

5 DECEMBER 9TH-13TH, 2009 SAN ANTONIO BREAST CANCER SYMPOSIUM V. TARGETED ANTI-ANGIOGENIC THERAPY (HER-2 NORMAL) Fina overa surviva resuts from the randomized, doube-bind, pacebo-controed, phase III AVADO study of bevacizumab pus docetaxe compared with pacebo pus docetaxe for the first ine treatment of ocay recurrent or metastatic breast cancer. DW Mies, United Kingdom, on behaf of the BO17708 study group. Previous untreated metastatic breast or ocay reapsed breast cancer patients were randomized to either docetaxe (100mg/m2) with pacebo, or combined with either bevacizumab at 7.5mg/kg or 15mg/kg, every 3 weeks, unti diseases progression. Were aowed to get bevacizumab with second ine chemotherapy on progression. Fina OS data: Median foow up of 25 months. Docetaxe + bevacizumab (15mg/kg) improved PFS compared to docetaxe + pacebo (10.1 vs. 8.2 months, HR 0.77, p=0.0061). Stratifi cation factors were time to reapse/prior taxane use, HR status, measurabe disease, and region. Stratifi ed HR was 0.67, p= OS at 1 year was aso improved (84% vs. 76% p=0.02). Improved Overa response rate (ORR) with 15mg dose of bevacizumab (64.1% vs 46.4%, p=0.0003). Important points: There was signifi cant crossover, with patients aowed to receive bevacizumab with second ine chemotherapy; this may have diuted the OS resuts at 2 years. Regardess, one year surviva may be an important endpoint in metastatic breast cancer therapy. Finay, the combination of docetaxe and bevacizumab at 15mg/kg may be a usefu combination for those patients requiring an immediate response from therapy, given the ORR data. RIBBON-II: a randomized, doube-bind, pacebo-controed, phase III tria evauating the efficacy and safety of bevacizumab in combination with chemotherapy for the second ine treatment of HER-2 negative metastatic breast cancer. A Brufksy, University of Pittsburgh, on behaf of coauthors. Previousy treated metastatic breast cancer patients stratifi ed by hormone status, choice of second ine chemotherapy, and interva to progressive disease on fi rst ine treatment. Assigned to second ine chemotherapy (investigator choice): 45% received taxanes, 21% received gemcitabine, 21% received capecitabine, 13% received vinorebine. Randomized 2:1 to receive bevacizumab (15mg/m2 q 3weeky or 10mg/m2 q2weeky), or pacebo in combination with second ine chemotherapy. Treated unti progression. 5

6 SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 9TH-13TH, 2009 Taxanes SOLTI Mutinationa, doube bind, randomized, pacebo-controed phase IIb study J Basega, Spain, on behaf of coauthors. Gemcitabine Capecitabine Vinorebine Addition of bevacizumab to second ine chemotherapy improved PFS (7.2 vs. 5.1 months, HR 0.78, p=0.0072). OS not improved (but interim anaysis with ony 57% of events.) Benefi t was independent of chemotherapy (except perhaps vinorebine). Locay advanced or metastatic breast cancer patients (with one or ess prior treatments) randomized to capecitabine (1000mg/m2 po bid, 14 days on in 21 day cyce), pus either pacebo or sorafenib 400mg po bid. 60% of patients had prior taxane therapy. Improved PFS with combination of capecitabine + sorafenib compared to capecitabine aone (6.4 vs. 4.1 mos, HR 0.58 p=0.0006). However, hand foot syndrome was significanty increased with the combination (89% vs. 63%) and 45% of these in the combination arm were grade 3 events. The decision is to now study this combination in a Phase III tria. ANTI-ANGIOGENIC THERAPY TAKE HOME MESSAGE Modest benefi t of adding an anti-angiogenic to chemotherapy for metastatic disease. The benefi t is most striking in fi rst ine, but it is aso seen in the second ine setting. Anti-angiogenics (incuding muti-targeted TKIs) aone have imited activity in breast cancer. The ack of an OS benefi t sti imits the use of these drugs in Canada. One may consider the combination of chemotherapy and an antiangiogenic (such as bevacizumab) for patients who wi benefi t from a higher response rate. Need to deveop predictive biomarkers for the use of these agents. 6

7 DECEMBER 9TH-13TH, 2009 SAN ANTONIO BREAST CANCER SYMPOSIUM VI. TARGETED ANTI-HER-2 THERAPY (HER-2 POSITIVE) Phase III randomized tria comparing doxorubicin and cycophosphamide foowed by docetaxe with doxorubicin and cycophosphamide foowed by docetaxe and trastuzumab with docetaxe, carbopatin and trastuzumab in Her2neu positive eary breast cancer patients: BCIRG 006 Study. D Samon, UCLA Caifornia, on behaf of BCIRG006 Investigators. Adjuvant trastuzumab (Herceptin ) tria. AC-T (adriamycin, cycophosphamide chemotherapy x 4, foowed by docetaxe x 4) versus AC-TH (AC foowed by docetaxe + Herceptin ), versus TCH (docetaxe, carbopatin, Herceptin ). Herceptin continued for one year. 65 month update: Improved DFS with both Herceptin containing arms, compared to AC-T chemotherapy aone. Independent of ymph node status (high/ow risk). Improved OS with both Herceptin containing arms, compared to AC-T chemotherapy aone. Independent of ymph node status (high/ow risk). DFS (primary endpoint) AC-TH: 84% (HR 0.64, p<0.001) TCH: 81% (HR 0.75, p=0.04) AC-T: 75% Number of DFS events sighty higher in TCH arm compared to AC-TH (214 vs. 185). Metastatic event aso higher (144 vs. 124). OS AC-TH: 92% (HR 0.63, p<0.001) TCH: 91% (HR 0.77, p=0.038) AC-T: 87% Number of OS events sighty higher in TCH arm compared to AC-TH (113 vs. 94). Breast cancer death events aso higher (97 vs. 83). Anaysis of topoisomerase 2a tumour status suggested that Herceptin benefi t was imited to topoisomerase 2a non co-ampified tumours. This remains controversia. Grade 3/4 congestive heart faiure events remained higher in AC-TH arm compared to TCH (21 versus 4). Leukemia events aso higher in both AC containing arms versus TCH (7 versus 0). Resuts of chemotherapy aone, with sequentia or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer tria EA Perez, Mayo Cinic Forida, on behaf of NCCTG/NSABP co-triaists. Randomized HER-2 positive patients to either A: AC-T (adriamycin, cycophosphamide x 4 foowed by pacitaxe x 12) or B: AC-T-H (AC x 4, foowed by P x 12, foowed by Herceptin x 52) or C: AC-TH-H (AC x 4, foowed by P concurrent with H x 12, foowed by H for another 40.) 5 year update: 5 years DFS improved by Herceptin arms. AC-T: 71.9% AC-T-H: 80.1% Concurrent H had better DFS vs. Sequentia: AC-TH-H: 84.2% AC-T-H: 79.8% 7

8 SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 9TH-13TH, 2009 EGF Updated surviva anaysis of a randomized study of apatinib aone or in combination with trastuzumab in women with HER-2 positive metastatic breast cancer progressing on trastuzumab therapy. KL Backwe, Duke University, Durham. On behaf of EGF group. HER-2 positive metastatic breast cancer patients with progression on: anthracycines, taxanes and progression on most recent trastuzumab regimen, randomized to: apatanib 1500mg po od or apatanib 1000mg po od + trastuzumab (4mg/kg 2mg/kg) weeky anaysis: improved PFS (primary endpoint) in combination arm and 2.9 months improvement in OS. Current updated anaysis: improved median OS in apatanib + trastuzumab arm, compared to apatanib aone (14 vs. 9.5 mos, HR 0.74, p=0.026). Benefit seen despite 52% crossover. Heaviy pre-treated (on average 3 prior trastuzumab regimens). We toerated (8% grade 3/4 events compared to 7% apatanib aone). TARGETED HER-2 THERAPY TAKE HOME MESSAGE Adjuvant Trastuzumab given concurrenty with chemotherapy (taxane portion of treatment or with non-anthracyine regimen) appears to be more effective than initiating trastuzumab after chemotherapy. A non-anthracycine approach (TCH), whie effi cacious, may not be as effective as using a regimen with an anthracycine and trastuzumab in the HER-2 positive popuation overa. Need to vaidate use of Topo-2a as a marker for therapy, and deveop trias for those who are Topo-2a co-ampifi ed. Metastatic The combination of trastuzumab and apatinib appears to be synergistic, even in patients who have been heaviy pre-treated with trastuzumab therapy. We need to vaidate the use of trastuzumab beyond progression. We have imited data for using the combination of trastuzumab and apatanib (HER-2 dua targeted approach), in combination with chemotherapy. Further trias are required to compare the HER-2 dua targeted approach with standard metastatic regimens containing chemotherapy and a HER-2 targeted agent. This newsetter was supported by an unrestricted educationa grant from Roche Canada. January