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BREAST CANCER Updated May 2017 by Dr. Veitch (PGY-5 Medical Oncology Resident, University of Calgary) Reviewed by Dr. Jan-Willem Henning (Staff Medical Oncologist, Tom Baker Cancer Centre, University of Calgary), Dr. Eitan Amir (Staff Medical Oncologist, Princess Margaret Cancer Centre, Toronto) and Dr. Christine Simmons (Staff Medical Oncologist, BC Cancer Agency Vancouver) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH
EPIDEMIOLOGY - Most common life threatening cancer among women; second most common cause of cancer
mortality - Compared to white women, black women have lower incidence of developing breast cancer but
higher rate of breast cancer-related mortality due to higher incidence of triple negative disease, and presenting with more advanced disease
- Incidence increasing in economically developing countries possibly due to lifestyle changes (obesity, decreased physical activity), possibly due to increased awareness and improving diagnostic tools, and also changes to hormonal risks such as increasing nulliparity and older age at first pregnancy and reduced breast feeding. There is some element of overdiagnosis in countries with screening programs.
- Incidence decreasing in developed countries since 2002, likely as result of decreased HRT - Mortality decreased 30% over last 10 years in CA, US, UK most likely related to increased
screening and new therapies (also some of this is stage migration resulting from overdiagnosis)
RISK FACTORS - Risk Models
o Modified Gail Model: most widely used, calculates 5 year and lifetime risk of breast cancer based on various variables:
§ Age, age at menarche, age at first pregnancy, number of biopsies, presence of atypical hyperplasia, number of first-degree relatives w breast cancer, and race.
§ Underestimates risk if significant genetic predisposition o BRCAPRO, IBIS (Tyrer-Cuzick), BOADICEA: calculate risk based on risk of harboring
genetic mutation and have also been validated as general risk calculators. - Weak (RR<2X)
o FMHX post-menopausal cancer (excluding male or bilateral) o Higher SES o Nulliparity; later age of first birth (>30); late menopause (>55); early menarche (<15);
post-menopausal obesity; ETOH; Diet; long term HRT - Moderate (RR 2-4)
o Older age o NA and N European residence o FMHX Pre-menopausal BC o Personal HX BC: breast hyperplasia w/out atypia; mammographic density >50% breast
volume - Strong (RR >4)
o FMHX of 3 (+) relatives with pre-menopausal bilateral BC or pre-menopausal in mother, grandmother, sister, daughteror ovarian cancer in grandmother, mother, sister, aunt or male breast cancer at any age
o Evidence of genes (BRCA1/2; PTEN; TP53; CHD1; STK11; PALB2) § BRCA1: Cumulative risk by age 70:
• Breast: ~65%
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• Ovarian ~40% • 2X increase risk pancreas • 2-4X increase risk colon in patients <50yo. Risk equivalent to population
risk >50 yo. § BRCA2: Cumulative risk by age 70
• Breast: ~45% • Ovarian: ~11% • 5-9X increase risk of prostate • 3.51X increase risk pancreas
o Personal HX lobular carcinoma in situ o Breast atypical hyperplasia o Mammographic density >50% breast
PREVENTION & SCREENING - Lifestyle Changes
o Physical activity: 3 prospective studies showing recreational exercise can reduce incidence of breast cancer by 20-30%, especially among pre-menopausal
o Diet and weight change: less alcohol consumption and maintain healthy weight - Risk-Reducing surgery:
o Oophorectomy: Recommended for BRCA carriers before age 40 (decreased ovarian risk, breast cancer risk, all-cause AND ovarian cancer-specific mortality)
o Bilateral mastectomy: decreases risk of breast CA >90% for high risk/BRCA patients - Medical (Chemoprevention):SERM and AI effective for risk of ER positive DCIS and IDC among
women with elevated risk using model (e.g. Gail) o Tamoxifen: EBCTCG trial showed decreased risk of 39% for contralateral breast cancer
in patients on 5 years adjuvant TAM at 15- years follow up § NSABP BCPT P-1: Women with 5 year risk (by Gail) >1.66% or LCIS received
TAM for 5 years vs. Placebo. 7-year FU showed decrease risk of invasive breast CA 43% (62% hormone positive). NO effect on overall mortality
o Raloxifene: MORE and CORE trial showed decrease incidence of invasive breast cancer by 69-72%
§ STAR compared TAM to Raloxifene: No difference at 4 years follow up, however at 8 years follow up Raloxifene retained 76% of effectiveness in reducing risk of invasive cancer with less toxicity (VTE, endometrial CA)
o Exemestane: NCIC CTC MAP.3 Exemastane vs. placebo 65% risk reduction for invasive breast cancer (73% for hormone positive)
o Anastrozole: IBIS-2 - ANA vs. placebo - The predicted cumulative incidence of all breast cancers after 7 years was 5.6% in the placebo group and 2.8% in the anastrozole group (significant)
TRIAL PATIENTS (N) COMPARISON RR RR+ (hormone +) STAR 19 747 Raloxifine vs. TAM 1.24 NA MAP.3 4 560 Exemestane vs. Placebo 0.35 0.27 IBIS II 1 920 Anastrazole vs. Placebo 0.50 0.42 Italian 5 408 TAM vs. Placebo 0.84 0.61 Royal Marsden 2 471 TAM vs. Placebo 0.78 0.48 IBIS 7 145 TAM vs. Placebo 0.73 0.66 BCPT P-1 13 338 TAM vs. Placebo 0.57 0.38
- Screening: Data from evaluation of RCT published in 2002 suggests 23% reduction in breast cancer mortality in women ages 50-70, and 15% reduction for ages 40-50. Updated evaluation in 2009 showed 14% for women aged 50-59, and 32% 60-69. (Nelson et al 2009) – no overall mortality reduction (Cochrane Database)
o Modalities
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o Digital Mammographic Imaging Screening Trial (DMIST): compared digital images with film screen images. Overall, no difference in diagnostic accuracy, however digital was superior in detection of malignancy among pre- or peri-menopausal women, women <50, and women with dense breast tissue
§ Population based study of two-view film-screening mammography vs. digital in Oslo found sensitivity of 77% with digital vs. 62% with film screening.
o Digital breast screening tomosynthesis: 3D imaging similar to CT § >90% sensitivity, slightly greater radiation § No trial w direct comparison with DBT and routine screening
o Ultrasound (US): Detects and defines ambiguous lesions on mammography; characterizes palpable masses
§ NOT useful alone; increased sensitivity of mammogram by 25% in a study by ACRIN in select population (dense breast). Also had increased false positive rate
o Clinical Breast exam: In 2015, Canadian Task Force on Preventive Health Care and ACS recommend not performing clinical breast examination, given potential for false positive and lack of evidence for improved outcomes
o Breast self exam: has NOT been shown to increase detection of early-stage breast CA on population basis
o MRI: Utility in high risk population (see below) o Recommendations o Average risk age 50-74
§ Mammogram q2 years § Age 40-50 discuss w patient, q1 year if decide to screen. Decision based on
other individual risk factors (see above) (Canadian TOP guidelines). § Age 75 (+): consider individual health factors/life expectancy and patient
preference o High Risk Groups o BRCA mutation:
§ Who to screen: Varies provincially • Diagnosis of breast cancer before age 50, especially triple negative • Bilateral breast cancer • Breast and ovarian cancer in same patient • One (+) male family members with breast cancer • Multiple family members with breast or ovarian cancer • One family member who is positive for BRCA • Ashkenazi Jew with diagnosis of breast cancer
§ In general, screening begins at age 25 with annual mammography and MRI (usually 6 month alternating with mammogram) PLUS biannual clinical breast exam
• MRI when added to mammogram increases sensitivity from 25-59% to 80-100% (also decreased specificity from 93 to 73%)
• Adding MRI to mammogram is associated with a 70% reduction in lymph node positive or large invasive breast cancer
• Annual MRI also offered to untested first degree relatives of BRCA patient
o Other: Annual MRI is also recommended for Li-Fraumeni, Cowden, history of mantle radiation for treatment of lymphoma prior to age 30 based on extrapolation from data from BRCA studies
§ Consider annual MRI for women with lifetime risk >20-25% based on risk models that depend on family history NOT Gail.
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B) PRESENTATION & DIAGNOSIS
SYMPTOMS & SIGNS - SYMPTOMS:Palpable mass, unilateral nipple discharge, inflammatory breast cancer
(uncommon; see below), SX from metastatic disease (bone pain, RUQ pain) - Common Presentations: Often with positive screening examination or palpable mass.
INVESTIGATIONS - Laboratory (pre-treatment): Basic bloodwork (CBC, electrolytes, Creat) Liver Enzymes
(including ALP) - Diagnostic Procedures:
o All patients with a palpable area of concern should undergo triple diagnostic investigation (clinical, radiological and pathological). Screen-detected abnormalities can be simply followed up if appear benign or subjected to tissue diagnosis.
o Abnormal screening mammogram should have diagnostic mammogram (more views than standard 2 views in screening mammogram) +/- US
§ Normal mammogram should NOT delay DX if palpable mass o Biopsy non-palpable using fine wire localization o Biopsy for diagnosis: Core BX > FNA (does not provide enough tissue to differentiate
invasive from non-invasive or to do receptor testing)
PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: Majority is either infiltrating ductal carcinoma (IDC; 75%) or infiltrating
lobular carcinoma (ILC; 10%) or a combination o IDC easier to see mammographically vs. ILC o ILC has increased frequency of multifocality and higher incidence of bilateral involvement
and nodal involvement at time of diagnosis o Prognosis similar
- Common Metastatic Sites (de-novo metastatic disease rare except in node positive women):
o Bone: More common first site of mets for ER+, post-menopausal cancer (but 75% of all metastatic breast cancer patients develop bone metastases at some point in the natural history of their disease)
o Liver o Lung o Brain
- Relevant Molecular Biology: o Tumor size: greatest diameter. If multifocal use largest lesion not summation o Grade (based on nuclear size; tubule formation; #mitosis/hpf) I-III o Lymphvascular invasion o Margins (less of an issue than before; ASCO/ASTRO guideline) o LN (# resected, # positive) o Extranodal extension o ER/PR: IHC on core BX; may be done on surgical if results incongruent w histology
§ 0 (Allred 0-2); 1+ (Allred 3-4); 2+ (Allred 5-6); 3+ (Allred 7-8)l; also commonly reported as % only
o HER2/neu: overexpressed in ~15-20% § Initial IHC: 3+ positive; 2+ intermediate; 1+ negative § If 2+: move on to in-situ hybridization(look at ratio of HER2 signal to chromosome
17 centromere) - can be fluorescent, silver, dual-colour or chromophobe. • FISH ratio of >/=2 is considered positive (this was the cut-off used in
clinical trials looking at Herceptin) - Intrinsic Molecular Subtypes
o Have very limited effect on clinical practice, but provide information on tumour biology/ o Require availability of a gene expression assay or use immunohistochemical surrogate. o Specific gene expression signature with clinical characteristics; subtypes characterized
by IHC have >1 IHC profile
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o IHC used as surrogate to define molecular subtypes since genomic profiling on all patients not practical
§ Ki67 used as alternative marker of proliferation however has less clinical validity than molecular testing; on continuous distribution therefore challenge to define useful cutpoint
o Luminal A: ER/PR+; often low grade, low incidence of p53 mutation, associated with best overall prognosis
o Luminal B: ER+, PR+/-, with more expression of proliferation and HER2 related genes; often higher grade and less favorably prognosis compared w luminal A
o HER2: Demonstrates overexpression of genes within the ERBB2 amplicon. Frequently HER2+; ER/PR- or low; more often high grade and associated with more p53 mutations (40-80%)
o Basal-like: mimic basal epithelial cells by not expressing HR or HER2 related genes. Associated with the least favorable prognosis. BRCA1 associated cancers are often basal-like (BRCA2 include entire spectrum, often EGFR over-expressing and may express CK5/6.).
STAGING - Investigations
o For stage I –IIB: consider additional studies only if directed by signs or symptoms o If clinical stage IIIA (T3, N1, M0) consider: Chest CT, abdominal +/-pelvic diagnostic
CT or MRI, bone scan or PET/CT - Uses TNM staging system
o Tumour § T1 mic: <0.1mm § T1 0.1-2.0 cm (T1a: 0.1-0.5cm, T1b: 0.6-1.0cm, T1c: 1.1-2.0cm) § T2 2.1-5.0 cm § T3 >5 cm
o Nodes § Noi+ <0.2mm metasteses (single cells or isolated tumor cell clustering) § N1mi: micrometasteses 0.2- <2mm § N1 1-3 nodes § N2 4-9 noes § N3 >10
o Metastases § MX unknown § M0 none § M1 present
- Stage o IA: T1N0M0; IB: T0-1N1micM0 o IIA: T0-1N1M0; T2N0M0; IIB: T2N1M0; T3N0M0 o IIIA: T0-2N2M0; T3N1-2M0; IIIB T4N1-2M0 o IV: any M1
C) TREATMENT Stage 0: Ductal Carcinoma in Situ (DCIS)
- Complete replacement of normal cells with spectrum of abnormal cells confined to the duct without invasion
- 15-50% will ultimately progress to invasive disease if not removed - Management: Detailed mammogram to obtain preoperative extent of disease
o Surgery for local control § RT if DCIS >1cm treated with BCS, and ALL with margins <5mm
o Mastectomy recommended for DCIS >5cm - NSABP: Tamoxifen shown to decrease occurrence of invasive and in situ disease when
combined with RT(Allred et al, 2012)
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o Contributes an additional 32% RRR in local recurrence and 53% for risk of contralateral disease 15 years after DX
o Not yet associated with improved OS LOCALIZED / ADJUVANT LOCAL DISEASE CONTROL STAGE I, II and III disease
- Total mastectomy o Adjuvant RT should be added if 4 (+) axillary nodes positive; clinical evidence for internal
mammary involvement; positive surgical margins; tumour >5cm o Consider if 1-3 LN+, or for tumour>5cm, especially with adverse pathology
- Breast conservation therapy (BCT): Demonstrated in NSABP B-06 to be equivalent OS to mastectomy
o RT: reduces absolute risk of ipsilateral breast recurrence by 30-40% down to 5-7% o Contraindications to BCT + RT: prior RT and connective tissue disease involving the skin
(i.e. scleroderma) - Clinically Node positive that are down-staged after NAT: SLN appropriateness
controversial o False negative rate remain >10% unless 3 (+) nodes examined
- SLND for clinically negative disease o AMAROS trial: Patients with T1-2 primary breast cancer and no palpable LAN were
randomized to receive either ALND or axillary RT in case of positive SLN § 5y axillary recurrence 0.43 after ALND vs. 1.19% after axillary RT. § Axillary RT resulted in significantly less morbidity
o ACOSOG Z011: Clinically node negative patients who underwent SN BX and had 1 or SN with metastases were randomized to ALND or no further axillaryspecific treatment
§ All patients were treated with lumoectomy and opposing tangential field irradiation
§ SNB alone had median 2 LN removed; ALND had median 17 § 5 y breast recurrence 3.7% (ALND) vs. 2.1% SLNB alone § 5y nodal recurrence 0.6% vs1.3% § 5yOS 91.9% vs 92.5% (ALND vs. SLNB)
ADJUVANT SYSTEMIC THERAPY
• General Approach: 3 Broad categories: HR+; HER2+; Triple negative • Decision to add is based on the risk of distant metastasis and the benefit of therapies to reduce
the risk o Gene expression profiles risk of recurrence, +/- benefit of chemotherapy
(e.g.MammaPrint or ONCOTYPE DX: below)
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HR+, HER2-
T1aNo
Endocrine RX or no therapy
T1a, N1mic or T1b, N0
Endocrine RX +/- CTX*
T1c-T3, N0 or Nmic, or 1-3
nodes positive
Endocrine RX +/-CTX; some
advocate CTX for all node *
T1-T3, >4 nodes +
Endocrine RX + CTX
HR+ HER2+
T1aN0
No adjuvant therapy or consider endocrine therapy
T1a, N1mi or T1b, N0-N1mic
Endocrine RX +/-CTX +
Trastuzumab
T1c-T3, N0-Nmic or node positive
Endocrine RX + Chemotherapy +
Trastuzumab
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*Recurrence scores may help with decision-making in appropriate patients (see ONCOTYPE below) ADJUVANT HORMONE
- Bottom Line General Approach: IHC 1+ (Allred 3-4) debatable benefit, usually offered treatment; IHC 2+ (Allred 5-6) and 3+ (Allred 7-8) should get treatment
o PRE-MENOPAUSAL
Triple Negaitve
T1aNo
No adjuvant treatment
T1a, N1mic or T1b, N0-Nmic
+/- CTX
T1c-T3, N0-Nmic or node positive
CTX
HR- HER2+
T1a N0
No adjuvant TX
T1a, Nmic or T1b, N0-Nmic
+/-CTX + Trastuzumab
T1c-T3, N0-N1mic or node positive
+ CTX + Trastuzumab
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§ Standard 5 years of TAM; if still pre-menopausal additional 5y TAM (ATLAS); if post-menopausal, consider AI
• In ATLAS: only 8% of patients were pre-menopausal therefore must consider generalizability of results.
§ Ovarian suppression (Surgery vs. LHRHa) +AI
SOFT/TEXT Pagani O, et al2014 JCO(32:5s)
Regimen TEXT: TAM + OFS X 5y VS. Exemestane + OFS X 5y • All women started with GnRH; given concurrently with CTX (if
given) • BL oophorectomy or irradiation as alternative after 6mo
SOFT: TAM X5y vs. TAM + OFS X 5y vs. Exemestane + OFS X 5y • Choice of OFS method
Primary Endpoint DFS (invasive recurrence local/regional/distant; invasive CL BC; Second non-breast invasive malignancy; Death w/out prior cancer event) Protocol amended in 2011 (before efficacy data available) for joint analysis with SOFT and TEXT
Inclusion/Exclusion Criteria
Pre-MP; <12w after surgery; planned OFS; +/- CTX
Size (N) 4690 (combined w SOFT) Results DFS: 91.1 vs. 85.3% at 5 y (3.8% difference) EX+OFS vs. TAM+OFS Toxicity AE comparable with post-MP women; early cessation of all assigned TX
more frequent w EX+OFS Conclusion EX+OFS vs TAM+OFS Other Comments Greater difference observed in women who received chemotherapy
(higher risk disease) as outcomes in lower risk very good regardless Study not designed initially to be combined therefore slightly different inclusion criteria (in SOFT had to remain pre-MP <8 mo. after CTX Greater benefit seen in pts under age 35 EX+OFS vs. Tam improved outcome by 5-7% but for those under age 35 improved outcome by 12% No Tamoxifen alone arm included in final analysis
o POST-MENOPAUSAL § 5y total primary (AI or TAM)
• EBCTC o TAM 5y (HR recurrence 0.61)
• ATAC o Anastrazole (ANA) v TAM (HR 0.9)
• BIG 1-98 o Letrozole (LET) v TAM (HR 0.88)
• ABCSG-12 *3 years treatment o ANA+OFS v TAM+OFS (HR 1.1)
§ Switch total 5y • ABCSG-8
o TAM/ANA v TAM (HR 0.85) • BIG 1-98
o TAM/LET v LET (1.05) o LET/TAM v LET (0.96)
• ITA o TAM/ANA v TAM (0.57)
• TEAM o TAM/Exemestane (EXE) vs EXE (HR 0.97)
• IES
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o TAM/EXE vs TAM o FIRST and only STUDY TO SHOW IMPROVEMENT IN OS until
ATAC AND ATLAS • NSAS BC-03
o TAM/ANA vs TAM (closed early) • ARNO 95
§ Extended Adjuvant • aTTOM (2013)
o TAM X5y à Continue vs. stop • ATLAS
ATLAS Davies C. et alLancet(2013) 381:805-16
Regimen 5y TAM à 5y TAM vs. Placebo Primary Endpoint Recurrence, BC mortality, overall mortality Inclusion/Exclusion Criteria
Early breast cancer (surgically resected); Tamoxifen (current or stopped within past year); clinically free of disease
• ER negative or unknown not included in final analysis of outcomes; were included for toxicity
Size (N) 12894; 6048 with ER unknown or ER negative were included, but subgroup analysis of 6846 women with ER + were reported on
Results Recurrence (10y post entry) 25.1 vs. 21.4% (5 vs. 10y) BC mortality (10y post entry) 15 vs. 12% Overall mortality (10y post-entry) 18.6 vs. 21.1%
Toxicity Conclusion For women with ER+ disease 10 vs. 5 years of TAM further reduces
recurrence and mortality, particularly after year 10 Other Comments Accrual stopped early due to benefit seen in MA.17
• MA. 17 o 5yTAM à LET vs Placebo (0.68) o Modest improvement in OS that was statistically significant for
node positive women • ABCSG-6a
o 5yTAM à ANA vs Placebo (0.62) • NSABP B-33
o 5y TAM à EXE vs Placebo (0.68) § Overall: Addition of AI (either 5y or switch) is associated w 3% fewer DFS events
(CL breast cancer, relapse, death from any cause)
Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomized trials
Lancet. 2015;386:1341-52.
Regimen • Meta-analysis on individual patient data Mechanism of Action of Experimental Drug
• .
Primary Endpoint • Any recurrence of BC, BC mortality, death without recurrence and all-cause mortality
Inclusion/Exclusion Criteria
• post MP women with ER+ early breast cancer in trials of 5y AI vs 5y TAM; of 5y AI versus 2-3y TAM plus AI to 5y
Size (N) • 31920 Results • 5y TAM vs. 5y AI: recurrence RR favored AI significantly during
years 0-1(RR0.64) and 2-4 (RR0.88); ns thereafter
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• 10y BC mortality lower w AI (12.1 vs 14.2% 2p = 0.009) • 5y AI vs. switch: RR favored AIwhile patients were on AI, but not
after switch. Breast cancer mortality reduction was ns • 5y TAM vs. switch: RR favored AI during years 2-4 (RR0.56) but
not thereafter, and 10-y BC mortality was lower with switch (8.7 vs. 10.1 2p = 0.015)
Toxicity • Compared to Tamoxifen, AIs are associated with greater risk of ischemic heart disease and bone fracture, but lower risk of venous thrombosis and endometrial carcinoma. Risk of cerebrovascular disease is similar. (Amir et al JNCI 2011)
Conclusion • Recurrence RR favors AI during time when treatment differs but not significantly thereafter.
• BC mortality was reduced both when treatment differed (RR0.79) and subsequently (RR0.89) and for all periods combined (RR0.86)
Interpretation • AI reduce recurrence rates by about 30% (proportionately) compared with TAM while treatment differs but not thereafter
• 5y of AI reduced 10y BC mortality rates by about 15% compared w TAM, hence by about 40% (proportionately) to no endocrine TX
• For patients at risk of early relapse (large tumour, high grade, nodal involvement and no chemo) upfront AI is the preferred approach. For other patients, a sequencing strategy may be the best balance between benefits and risks.
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ADJUVANT CHEMOTHERAPY
o Adjuvant online: Recurrence risk assessment tool, last updated 2006 o Criteria for consideration of chemotherapy (any or all of)
§ Tumor >3cm § LVI § Grade III § Weak/low ER/PR § Node positive
o HORMONE POSITIVE o CTX for luminal A disease has little evidence for anthracycline/taxane over AC,
CMF o Oncotype DX: Recurrence score generated based on mRNA level of several genes
within the tumour § Patients must be: Node negative, fit for chemotherapy, PLUS higher risk (varies
by province)
Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen
Trial Time Since Random Assignment
Primary Adjuvant
Sequencing
Extended Adjuvant
60-month strategy; median follow-up 100 mos Postmenopausal, HR (+)
TAM ANA TAM + ANA
60-month strategy Median follow-up 76 mos (monotx), 71 mos (switching) Postmenopausal, HR (+)
LET TAM LET (2 yrs), TAM (3 yrs) TAM (2 yrs), LET (3 yrs)
36 month strategy Median follow-up 47.8 mos Premenopausal, ER and/ or PR (+)
TAM + GOS ANA + GOS TAM + GOS + ZOL ANA + GOS + ZOL
Primary random assignment60 month strategy; median follow-up 72 mos Postmenopausal, ER(+)/PR(+), no chemo
TAM TAM (2 yrs), ANA (3 yrs)
Randomly assigned to 2-3 yrs tx (5 yrs total)Median follow-up 64 mos Postmenopausal, ER(+), Node (+)
TAM (2-3 yrs) TAM
ANA
Primary random assignment60 month strategy; Follow-up 61 mos Postmenopausal, ER and/or PR (+)
TAM (2½ yrs), EXE (2½ yrs)
EXE
Randomly assigned to 2-3 yrs tx (5 yrs total)Median follow-up 55.7 mos Postmenopausal, ER(+) or unknown
TAM (2-3 yrs) TAM
EXE
Randomly assigned to 1-4 yrs tx (5 yrs total)Median follow-up 42 mos Postmenopausal
TAM (1-4 yrs) TAM
ANA
Randomly assigned to 3 yrs tx (5 yrs total)Median follow-up 30.1 mos Postmenopausal, hormone responsive
TAM (2 yrs) TAM
ANA
5 yrs of TAM, randomly assigned to 60 mos of txMedian follow-up 64 mos Postmenopausal, HR(+)
TAM LET
Placebo
5 yrs TAM, randomly assigned to 36 mos of txMedian follow-up 62.3 mos Postmenopausal, endocrine responsive
TAM ANA
Placebo
5 yrs of TAM, randomly assigned to 60 mos of txMedian follow-up 30 mos Postmenopausal, ER or PR (+)
TAM EXE
Placebo
-5 -4 -3 -2 -1 0 1 2 3 4 5
BIG 1-9839
ATAC111
ABCSG-1222
ABCSG-859
ITA112
TEAM31
IES113
NSAS BC-038
ARNO 95114
MA.17115
ABCSG-6a116
NSABP B-33117
Fig 1. Schema of included trials. ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); mos, months; HR (!), hormone receptor–positive; TAM, tamoxifen; ANA,anastrozole; BIG, Breast International Group; FU, follow-up; monotx, monotherapy; LET, letrozole; yrs, years; ABCSG, Austrian Breast and Colorectal Cancer StudyGroup; ER (!), estrogen receptor–positive; PR (!), progesterone receptor–positive; GOS, goserelin; ZOL, zoledronic acid; ABCSG, Austrian Breast and ColorectalCancer Study Group; Chemo, chemotherapy; ITA, Italian Tamoxifen Anastrozole (trial); tx, therapy; TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE,exemestane; IES, Intergroup Exemestane Study; Unk, unknown; N-SAS, National Surgical Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, NationalSurgical Adjuvant Breast and Bowel Project.
ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer
www.jco.org © 2010 by American Society of Clinical Oncology 5Downloaded from jco.ascopubs.org on July 24, 2015. For personal use only. No other uses without permission.
Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
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Receptor-Positive Breast Cancer Paik et al 2006 JCO (3726-34)
Purpose
• Follow up to 21-gene recurrence score assay (Paik et al 2004) that quantified likelihood of distant recurrence to determine benefit of chemotherapy
Methods • RS was measured in tumors from TAM treated and TAM plus chemotherapy from NSABP B20 trial
• Cox proportional hazards models utilized to test interaction between chemotherapy and the RS
Primary Endpoint • DFS Inclusion/Exclusion Criteria
• Node negative, ER positive, HER2 negative breast cancer treated with TAM
Size (N) • 651 Results • Patients with high-RS (>/=31) had large benefit from chemotherapy
(RR 0.26 CI 0.13-0.53) • Patients with low RS (<18) derived minimal if any benefit (RR1.31 CI
0.46-3.78) Toxicity • NA Conclusion • RS both quantifies likelihood of breast cancer recurrence with
node-negative ER+ BC, and also predicts the magnitude of CTX benefit
Other Comments • Based on this trial high (>/=31), intermediate, and low (<18) scores were determined; all patients w high score receive combination chemotherapy, low should not, and intermediate to discretion of physician
• Follow up to the original article defining the RS: Paik et al 2004; NEJM 351: 2817-2826
TailoRx (Trial Assigning Individualized Options for Treatment)
NEMJ 2015; 373:2005-2014
Purpose • To look at intermediate RS patients Methods • P3 RCT
• Women with Oncotype DX recurrence score 11-25 randomized 1:1 receive combination chemotherapy followed by hormonal therapy
Primary Endpoint • DFS Inclusion/Exclusion Criteria
• Node negative, ER+, HER2-, breast cancer receiving hormones
Results • Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy.
• At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).
Conclusion • Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years
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with endocrine therapy alone. • The second part of the trial to be reported later
RxPonder
Purpose • To look at low volume (1-3) node positive disease with the aim of
avoiding overtreatment for all node positive patients Primary Endpoint • DFS Inclusion/Exclusion Criteria
• ER+, HER2-, low volume (1-3) nodes positive
Comments • Study difficult accrual due to discomfort with to giving CTX to node positive patients
Conclusion • Results still pending
o CHEMOTHERAPY PROTOCOLS § Principles
• Most studies involve women younger than 70y, therefore administration in elderly patients is based upon risk/benefit
• There is no apparent benefit in dose escalation with standard dose CTX in adjuvant chemotherapy
• Polychemotherapy is preferred and associated with greater benefits in women younger than age 50, with higher risk (node positive) and hormone negative disease
§ In general, 4-6 months of chemotherapy with both Anthracycline and Taxane is preferred for node-positive women
• Node-negative but large and/or grade 3 cancers, consider shorter regimens (e.g. DCx4)
§ Post-Menopausal: Relatively young and fit consider for same as pre-menopausal with similar stage and grade
• Older (>60), less fit may derive less benefit and more toxicity (13) • In general, trials conducted in patients <70 yo therefore this must be
taken into consideration § Cardiac Co-morbidities: Consider non-anythacycline if low LVEF
• Cumulative lifetime exposure should not exceed 480mg/m2 § TRIPLE NEGATIVE
• Associated with higher recurrence risk than HR+ • CTX strongly recommended for all T1cN0or higher stage • Younger, fit patients may also benefit for T1a and T1b tumors, although
absolute benefits are smaller • There is apparent benefit from dose dense therapy in this group.
§ HER2+ • Combination chemotherapy plus Trastuzumab (preferably given
concurrently with taxane-based chemotherapy) for T1cN0 or higher • Ideally chemotherapy regimen consists of taxane + anthracycline or TCH
(BCIRG 006) • Consider for T1bN0M0 especially if HR- given recurrence >25% and
dramatically reduced w treatment Adjuvant or Neoadjuvant chemotherapy regimens HER2 NEGATIVE
Doxorubicin/Cyclophosphamide X4 (Fisher et al 1990) “AC”
Docetaxel/Cyclophosphamide X 4 (Jones et al 2009) “DC” Docetaxel/Cyclophosphamide x 6 (Blum et al 2017) “DC” “ABC trial”
dd Doxorubicin/Cyclophosphamide X4 àdd Paclitaxel X 4 (Citron et al 2003)“ddAC-T” Doxorubicin/cyclophosphamide X 4 à Paclitaxel weekly X 12 (Sparanoet al 2008)“AC-
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T” Flurouracil/Epirubicin/Cyclophosphamide àDocetaxel“FEC-D” (PACS01) Docetaxel/Doxorubicin/Cyclophosphamide X 6 (Martin et al, 2005)“TAC” HER2 POSITIVE
Adjuvant chemotherapy (various) à 1 year Trastuzumab (Piccart-Gebhartet al 2005 (HERA))
Docetaxel/carboplatin/trastuzumab X 6 àTrastuzumab1y total(Slamon et al 2011) BCIRG-006
Doxorubicin/cyclophosphamide X4 à Paclitaxel weekly X 12 + Trastuzumab X 1y total (Perez et al 2011)
Paclitaxel/Trastuzumab weekly X 12 weeks àTrastuzumab 1y total (Tolanyet al 2013) Neoadjuvant only: Pertuzumab/Trastuzumab/Taxane X 12 weeks à
Doxorubicin/Cyclophosphamide X 4 àTrastuzumab 1y total (Gianni et al 2012)
Taxane-Based Combinations as Adjuvant Chemotherapy of Early Breast Cancer: A Meta-
Analysis of Randomized Trials De Laurentiiset al (2008) JCO 26:44-53
Methods • Studies were retrieved by searching the PubMEd database and
proceedings of major conferences. HR and 95% CI were extracted for DFSand OS from each trial
Inclusion/Exclusion Criteria
• Early breast cancer; adjuvant therapy; RCT comparing taxane-anthracycline based to anthracycline based alone
Size (N) • 13 studies incuded Results • Survival: (HR 0.85; 5-yr risk reduction 5% absolute)
• DFS:HR 0.83; 5yr risk reduction 3% absolute • Combination anthracycline/taxane was not superior to sequence
Toxicity • (e.g. common toxicities overall, common grade 3/4 toxicities) Conclusion • Addition of taxane to anthracycine improves DFS and OS of high
risk early breast cancer patients Other Comments • Benefit was independent of ER status, degree of nodal involvement,
type of taxane, age/menopausal status and administration schedule
Weekly Paclitaxel in the Adjuvant Treatment of Breast Ca Sparano et al NEJM (2008) 358:1663-71
Methods • 2 X2 trial design following 4 cycles of DC; paclitaxel q 3 weekly X4 vs.
paclitaxel weekly X12 vs. docetaxel q 3 weekly X4 vs. docetaxel weekly X12
• Primary endpoint OS Inclusion/Exclusion Criteria
• T1-3N1-2, or high risk node negative (T2-3) within 3 months of surgery, any HER2
Size (N) • 4950 Results • Weekly paclitaxel and q3 weekly docetaxel provided superior DFS
• Weekly paclitaxel improved OS compared to q3 weekly paclitaxel Toxicity • Grade 2, 3, 4 neurpathy was more frequent with weekly paclitaxel than
with paclitaxel every 3 weeks Conclusion • Weekly paclitaxel after standard adjuvant chemotherapy with DC
improves DFS and OS in women with breast cancer
Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer (HERA)
Piccart-Gebhartet al (2005) NEJM 353: 1659-72
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Regimen • Randomized to one or two years of trastuzumab, q3wk vs. observation following physician choice chemotherapy
• Bolus 8mg/kg once, 6mg/kg each subsequent treatment Mechanism of Action of Experimental Drug
• Monoclonal antibody to extracellular domain of HER2neu (transmembrane tyrosine kinase))
Primary Endpoint • DFS Inclusion/Exclusion Criteria
• HER2+ • Early stage invasive BC; node positive or node negative with T >1cm • Completed locoregional therapy with minimum of 4 courses of
chemotherapy either neoadjuvant or adjuvant • Normal LVEF (>55)
Size (N) • 5081 Results • Survival: 2 yr OS not statistically significant (96% vs 95.1%)
• DFS:2 yr DFS for 1yrtrastuzumab 85.8 vs. 77.4 for observation (HR 0.54)
Toxicity • (e.g. common toxicities overall, common grade 3/4 toxicities) Conclusion • Addition of trastuzumabfor 1 year after adjuvant chemotherapy
significantly improves DFS among women with HER2+ breast cacer Other Comments • This trial did not look at concurrent administration with Taxane
(addressed in Romondet al 2005 NEJM 353:1673-84) • Small follow up period unable to detect OS difference since OS was so
high in both groups ADJUVANT BISPHOSPHONATES
• Adjuvant bisphosphonates should be considered for postmenopausal women who are deemed candidates for adjuvant chemotherapy.
• For adjuvant bisphosphonates, zoledronic acid 4mg q6 months x 5 years and clodronate 1600mg po daily for 2-3 years are recommended (as per ASCO/CCO 2016 Adjuvant Bisphosphonate guidelines).
Adjuvant Bisphosphonate treatment in early breast cancer: meta-analysis of individual patient
data from randomized trials Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Lancet 2015; 386: 1353-61.
Methods • 18,766 women from early breast cancer trials randomized to bisphosphonate or control
Size (N) • 18,766 Results • Overall, decreased bony recurrence with bisphosphonate use (RR 0.83,
p=0.004) • Overall, decreased breast cancer mortality (RR 0.91, p =0.04) • Overall, reduction in any recurrence (RR 0.94, p=0.08) • In premenopausal women, there was no significant beneficial outcome
of bisphosphonates. • However, in postmenopausal women, the benefits were highly
significant: breast cancer mortality (RR bony recurrence 0.82, p=0.002), (RR 0.72, p=0.0002),
Toxicity • Grade 2, 3, 4 neurpathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks
Conclusion Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.
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NEOADJUVANT THERAPY (NAT)
- Principle o Outcomes of neoadjuvant = adjuvant for DFS and OS (NSABP B18) with higher chance
of achieving breast conservation. - Advantages
o Allows immediate assessment of tumour response o Allows evaluation of new and novel agents o May allow for earlier control of micrometastases o May allow for option of BCS o May render inoperable disease operable o May improve chances of obtaining clear surgical margins with 1st operation
- Bottom Line General Approach: Chemotherapy regimens the same neoadjuvant as for adjuvant
- Candidates for NAT: o Inflammatory BC
§ Clinical DX; at a minimum the following are required • Rapid onset of erythema, edema and/or peaud’orange with or without
underlying mass; Duration of HX < 6mo; Erythema at least 1/3 of breast; pathologic confirmation of invasive carcinoma
o Locally advanced: Definition varies among trials. Canadian Consensus definition: § T3 or T4 with any clinical N status § Any size tumor (T) with N2 or N3 disease
o Other: May be considered in any patient who has clinical features that make it certain they will need systemic therapy. Especially if it may mean BCS vs. mastectomy
- Work Up: Histology (ER, PR, HER2 on core; breast imaging; imaging of the ipsilateral axilla with FNA of any suspicious nodes; clinical staging
o In clinically stage IIB (+) get metastatic imaging (CXR, US)
NSABP-B18 Fisher et al (1997) JCO 15: 2483-2493
Regimen • Post-operative AC vs pre-operative AC Primary Endpoint • Clinical complete response (cCR); Pathologic complete response
(pCR) Size (N) • 1523 Results • Response Rate:Breast tumor size reduced in 80%; 36% had cCR;
26% with cCR had pCR • Clinical Decision making: 12% more lumpectomies performed in
the pre-surgery group Toxicity • NA Conclusion • Pre-operative therapy reduced the size of most breast tumors and
decreased the incidence of positive nodes • Greatest increase in lumpectomy after NAT occurred in women with
tumors > or = 5cm Other Comments • 9 yr follow up (Wolmark et al 2001) Demonstrated patients with pCR
had better OS vs. those who did not
NSABP-B27 Bear J Clin Oncol 21:4165-4174, 2003, J Clin Oncol 24:2019-2027, 2006
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Regimen • Either four cycles of preoperative AC followed by surgery (group I), or four cycles of AC followed by four cycles of docetaxel, followed by surgery (group II), or four cycles of AC followed by surgery and then four cycles of docetaxel (group III).
Primary Endpoint • DFS (OS secondary) Size (N) • Women (N = 2,411) with operable primary breast cancer Results • Addition of T to AC did not significantly impact DFS or OS. There
were trends toward improved DFS with addition of T. • The addition of T reduced the incidence of local recurrences as first
events (P = .0034). • Preoperative T, but not postoperative T, significantly improved DFS
in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007).
• Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001).
• Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001).
Conclusion • The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally
advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere) Gianni L et al (2012) Lancet Oncol. 13:25-32
Regimen • Open label P2 study; 1:1:1:1 randomization to 4 neoadjuvant cycles
of trastuzumab/docetaxe (Goup A)l vs. pertuzumab/trastuzumab/docetaxel (B) vs. pertuzumab/trastuzumab (C) vs. pertzumab/docetaxel(D)
Primary Endpoint • Pathologic complete response (pCR) Size (N) • 417 Results • pCR: 45.8% (Group B); 29% (A); 24% (D); 17% (C) Toxicity • Most common AE grade 3 (+) were neutropenia, febrile neutropenia,
and leucopenia. Serious AE were similar in all groups with the exception of Group C with fewer serious adverse events.
Conclusion • Combination of pertuzumab + trastuzumab + docetaxel achieved the highest pCR
Other Comments • Based on results of this trial US FDA issed accelerated approval for neoadjuvant HER2 disease, stage II or III. In general, patients should also receive post-operative anthracycline and complete 1 year of trastuzumab
• To date, no evidence for DFS or OS • Pertuzumab and trastuzumab without chemotherapy eradicated
tumours in a proportion of women with favorable safety profile LOCAL RECURRENCE
Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR) Aebiet al Lancet Oncol 2014;15:156-63
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Regimen Open label randomized trial comparing chemotherapy (physician choice) vs. no chemotherapy
Primary Endpoint DFS Inclusion/Exclusion Criteria
Patients with histologically proven and completely excised isolated locoregional recurrences after unilateral breast CA who had undergone lumpectomy or mastectomy with clear surgical margins Patients with ER+ received hormone therapy, anti-HER2 optional
Size (N) 162 patients (85 randomized to CTX; 77 to no chemotherapy) Results Median follow up 4.9 years 28% (CTX) vs. 44% (no CTX) had DFS
events 5y DFS was 69% (CTX) vs 57%%; HR 0.59 (p=0.046) Analysis of DFS according to ER status were not statistically significant (p=0.43); ER positive patients did not have significant benefit for DFS
Toxicity 15% of CTX group had serious AE: most common neutropenia, febrile neutropenia and intestinal infection
Conclusion Adjuvant CTX should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is ER negative
Other Comments Data has not matured yet to analyze OS (underpowered to perform this analysis.)
D) REFERENCES
- ASCO-SEP Medical Oncology Self-Evaluation Program. Fourth Edition. 2015. 114-153. - BC Cancer Agency Treatment Guidelines - Alberta Health Services Cancer Treatment Guidelines - Towards Optimized Practice - Oeffinger KC, GOntham ET, Etzioni R, et al. Breast Cancer Screening for Women at Average
Risk: 2015 Guideline Update from the American Cancer Society. JAMA 2015;314(15):1599 - Canadian Task Force on Preventive Health Care. Recommendations on screening for breast
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with BRCA 1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003; 72(5):1117
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E) ABBREVIATIONS • ALND: Axillary Lymph Node Dissection • BC: Breast Cancer • BCT: Breast Conserving Treatment • BSE: Breast Self-Exam • BX: Biopsy • FMHX: Family History • HRT: Hormone Replacement Therapy • HX: History • IDC: Invasive Ductal Carcinoma • LN: Lymph Node • RT: Radiation therapy • SLN: Sentinal Lymph Node • SLND: Sentinal Lymph Node Dissection • SX: Symptom • TAM: Tamoxifen
