Approach to Breast cancer

Dr. Jan-Willem Henning MBChB FRCPCMedical OncologistTom Baker Cancer CentreApproach to Breast cancer

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Halsted Radical MastectomyFirst reported in 1882, the radical mastectomy was the mainstay of surgical treatment for 70 years5

SURGERYCHEMORADIATIONSequential therapy

CHEMOSURGERYRADIATIONSequential therapy Epidemiology

2/5 Canadians will develop cancer in their lifetime Canadians will die of cancer63% of Canadians diagnosed with cancer will survive at least 5 years

1 in 9 lifetime risk for Canadian women to develop Breast Cancer

Average Lifetime risk of 12%

1 in 29 women will die from breast cancerIn Canada ** Lung cancer is the most common cause of cancer death in women, breast cancer is the second most common

Canadian statsCanadian Cancer Statistics 20141111Canadian Stats on Breast CancerIt is estimated that in 2015:25,000 women will be diagnosed with breast cancer. This represents 26% of all new cancer cases in women in 2015.5,000 women will die from breast cancer. This represents 14% of all cancer deaths in women in 2015.On average, 68 Canadian women will be diagnosed with breast cancer every day.On average, 14 Canadian women will die from breast cancer every day.220 men will be diagnosed with breast cancer and 60 will die from it.Canadian Breast Cancer Society 2015

Canadian Cancer Statistics 2014Risk Factors in Breast Cancer

15Risk Factors: Cancer Society of Canada

Canadian Breast Cancer Society 2015

ANNALS OF SURGERY Vol. 237, No. 4, 474482 2003.17Systemic Therapies for Breast Cancer

Systemic Therapies in Breast CancerChemotherapyAnthracylines, taxanes, platinums (TCH), and others

Targeted therapyTrastuzumab, Trastuzumab-Emtansine, Pertuzumab

Endocrine therapyTamoxifen Aromatase InhibitorsGnRH analogues19Her 2-Goals of Adjuvant TherapyTo prevent Breast Cancer RecurrenceTo improve overall survivalDoes it work?EBCTCG meta-analysis has shown a decrease in disease specific mortality Relative risk reduction therefore women at highest risk derive the greatest benefitShould all Women with Breast Cancer receive Chemotherapy?How do decide an individuals risk for recurrence?Prognostic factorsClinicopathologic factorsTumor sizeHistologic gradeLymph node statusLymphovascular invasionPatient ageER/PR statusHer2 status?Ki67Risk calculators Adjuvant!/Cancermath.net/FinprogMolecular profile Oncotype Dx/Mammaprint

How do we determine the benefit from adjuvant therapy?Predictive factorsER/PR statusHer 2 statusAdjuvant!Oncotype DxTwo Important Questions Asked by Patients

24Will my cancer come back?Do I need chemotherapy?24Newly diagnosed patients with ER-+, HER2-, N0 early invasive breast cancer

The Oncotype DX Breast Cancer AssayDetermines the expression of21 specific genes from an individual patient's tumourPrognostic: provides information about the individual risk of recurrence at 10 yearsPredictive: predicts the likelihood of benefit of chemotherapy in patients who will receive endocrine therapy25

The Oncotype DX Breast Cancer Assay can determine the gene expression of 21 specific genes from an individual patients tumourThe Recurrence Score (0 to 100) directly correlates with the rate of distant recurrence within 10 years, and classifies patients into low (80% risk of recurrence

Benefit:risk ratio very favorable for systemic chemotherapy

The greater the risk, the more benefit:-Reduction of Recurrence-Improving Survival (OS)

Adjuvant Chemotherapy

Principles of ChemotherapyOxford Overview (2005-2011): EBCTCG LancetMeta-analysis 100,000 randomly selected patients treated in different RCTsNon-taxanes vs. Taxanes 44,000Different Anthracyclines 6,000Anthracyclines compared to CMF 18,000No chemo vs. poly-chemotherapy 32, 000

Principles of ChemotherapyOxford Overview (EBCTCG) Lancet 2011updateBenefit for Anthracycline and Taxane-based chemotherapy (Poly-chemotherapy).Regardless of nodal, ER, or PR statusMolecular Diagnostic Assays may identify ER+ tumors that may not warrant Chemotherapy

FEC-D (3 cycles of 5-FU, Epirubicin and Cyclophosphamide, followed by 3 cycles of Docetaxel) given IV for 18 weeksRisk of Breast CA Recurrence 35-40%Risk reduction (benefit) 10-12% with chemoRisk of Breast CA Mortality 15-25%Absolute Survival Benefit of 8-10% with chemoFor our case:Additional Benefit with Adjuvant Endocrine TherapySum total of Benefit for both chemo and endocrine therapyIn Breast Oncology: 1+1 is not 2But the tumor ER+Extended Tamoxifen: ASCO Guidelines 2014

Adjuvant Endocrine Therapy in 2014Tamoxifen (5+5)10yMenopausal status unknown: tamoxifen 10yOvarian Function Suppression (OFS)

Tamoxifen alone (AI contra-indicated) 10yAI Upfront 5 ySwitch tamoxifen 2-3y followed AI up to 5yTamoxifen 5y extended AI up to 5yIntolerance: switchPre-or Perimenopausal WomenPost-menopausal WomenExtended Tamoxifen: ATLAS

Extended Tamoxifen: ATLAS

Reduction: Breast Cancer Recurrence and mortality, as well as reduction in overall mortality for 10y group.Carry Over EffectCumulative Risk Recurrence for years 5-14: 21.4% vs 25% Mortality (RR) years 5-14: 12.2% vs 15.0%Absolute OS benefit 2.8%Increase VTE and Endometrial CADecrease IHDStroke equivocalTamoxifen: SERM (Selective Estrogen Receptor Modifier)

Tamoxifen20 mg po dailyReduces risk of breast cancer recurrence by 40% and breast cancer mortality by 35% (Relative Risk, Meta-analysis EBCTCG).Antitumor effect: estrogen receptor antagonistPartial estrogen agonistBone helps prevent bone demineralizationUterus causes endometrial hyperplasia which leads to an increased risk of endometrial cancer?lowers risk of CVD favorable effect on lipids

Tamoxifen side-effectsHot FlashesCommon?due to an anti-estrogenic effect on the CNS causing thermoregulatory dysfunctionVenous thromboembolic diseaseRisk may be as high as 2 3 fold over normalRisk factors include prior surgery, fracture and immobilizationConflicting data on arterial thromboembolism

Endometrial cancerMajority present with vaginal bleedingIn the NSABP P1 study nearly all occurred in >50 age groupRisk increases with longer duration of tamRisk decreases with discontinuation of tamApproximate risk is 3 fold higher than normal

Tamoxifen side-effectsOther uterine pathology Fibroids, polypsMenstrual irregularity in pre-menopausal womenVaginal dischargeSexual dysfunctionCataracts controversial but may be slight increased risk-recommend annual eye examination

Aromatase Inhibitors

Aromatase InhibitorsLetrozole & anastrozoleNon-steroidal inhibitorsExemestaneSteroidal inactivatorBlock aromatization of androstenedione and testosterone to estroneAromatase is in skeletal muscle, adipose tissue and breast tissueAromatase inhibitor Side-effectsLack partial agonist activity therefore do not see side-effects such as an increased risk of thromboembolic disease and endometrial hyperplasia/carcinoma

Not indicated in women with functioning ovaries

Negative effect on bone densityCa and vit D +/- bisphosphonate, monitor BMD

MSK45% experience arthralgias/stiffness NSAIDs

Hot flashesVenlafaxine, gabapentin

Vaginal dryness / dyspareuniaVaginal moisturizers (Replens), vaginal lubricants

OFS in Premenopausal Patients

Her-2 Positive Breast Cancer: 15-20%

Presence increase relative risk of recurrence by 30%.Immunohistochemistry staining, indertemined followed by CISH/FISH.Trastuzumab added benefit relative risk reduction.Treatment for 1 year.Sequentially with Anthracyclines, but concurrently with Taxanes.Risk of cardiomyopathy

Adjuvant Her-2 + Breast CaTreatment per StageStage I: BCS + RT/Mastectomy (SNLD) +/- Tamoxifen and/or Aromatase Inhibitors (AIs)

Stage II: (High risk node and all node +) BCS+RT/Mastectomy+SNLD +or- AXLND Systemic(Chemo/Endocrine/Trastuzumab) Additional locoregional XRT (Mastectomy) Stage III: (Locally Advanced Breast Cancer) Neoadjuvant systemic therapies/Trastuzumab, Mastectomy+AXLND Locoregional XRT.

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