Breast Cancer

BREAST CANCER

Part 1: Molecular Biology

DEVITA CLUB

Ann Meredith U. Garcia, MD, DPCP

HEREDITARY BREAST CANCER somatic genetic alterations — vast majority of

breast cancers appear to occur sporadically germline mutations — 10% familial forms — 20% (to 30%)

BREAST CANCER SUSCEPTIBILITY GENES & LOCI

RARE HIGH-PENETRANCE GENES

BRCA1 and BRCA2 approximately 50% of all dominantly inherited

hereditary breast cancers relative risk — 10 to 30x lifetime risk — 85% tumor suppressor genes — primary action

loss of heterozygosity (LOH) via loss, mutation, or silencing of the wild type BRCA1/BRCA2 allele → defective DNA repair → rapid acquisition of additional mutations, particularly during DNA replication

RARE HIGH-PENETRANCE GENES

BRCA1 and BRCA2 BRCA1-related breast cancers

younger women more aggressive features

↑ histologic grade ↑ proliferative rate aneuploidy absence of ER/PR and HER2 (triple-negative

phenotype)

RARE HIGH-PENETRANCE GENES

OTHER HIGH-PENETRANCE GENES TP53, PTEN, STK11/LKB1, and CDH1

8 to 10x ↑ in risk of breast CA collectively account for <1% of cases of

breast CA autosomal dominant tumor suppressors

BREAST CANCER SUSCEPTIBILITY GENES & LOCI

RARE MODERATE-PENETRANCE GENES

CHEK2, ATM, BRIP1, and PALB2 2 to 3x relative risk of breast CA mutation frequencies — 0.1% to 1% collectively account for approximately 2.3%

of inherited breast CA known roles in signal transduction and DNA

repair in close association with BRCA1 and BRCA2

BREAST CANCER SUSCEPTIBILITY GENES & LOCI

COMMON LOW-PENETRANCE GENES

15% to 40% of breast CA <1.5x relative risk may become clinically relevant in their

interactions with other high-, moderate-, and low-risk genes

SPORADIC BREAST CANCERSOMATIC CHANGES causes

erroneous DNA replication exposure to exogenous and endogenous

mutagens passenger mutations

vast majority of identified somatic DNA mutations

do not contribute to oncogenesis driver mutations

confer a growth advantage on the cell found in candidate cancer genes (CAN)

SPORADIC BREAST CANCERSOMATIC CHANGES gene amplification — common

17q12 amplicon (HER2) — best example more aggressive tumor phenotype

11q13 (CCDN1) and 8q24 (MYC), 20q13 amplicons prognostic significance important in DNA metabolism and maintenance of

chromosomal integrity response to anticancer therapy might be modulated

by the presence of particular amplicons frequent in HER2 amplified tumors

GENE EXPRESSION PATTERNSMOLECULAR CLASSIFICATION luminal A and B tumor types — typically

ER/PR positive HER2 gene-amplified tumors basal-like (due to expression of basal keratins)

— typically lack ER, PR, and HER2

ESTROGEN SIGNALING ER — overexpressed in as

many as 70% of invasive breast cancers

level of ER expression — highly effective predictor for response to antiestrogens

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2/EGFR2/ErbB2)

member of a family of receptor tyrosine kinases HER2 protein

exists in a closed conformation and has no ligand preferred partner for dimerization with HER1, -3, and -4

HER2 amplification or protein overexpression 20% to 30% of invasive breast cancers associated with deregulation of G1/S phase cell

cycle control via: up-regulation of cyclins D1, E, and cdk6 p27 degradation

clearly associated with accelerated cell growth and proliferation, poor clinical outcome, and response to trastuzumab

RAS/RAF/MEK/MAPK PATHWAY• activated by multiple

growth factor receptors (ErbB1 and ErbB2) and several intracellular tyrosine kinases such SRC and ABL

• activated RAS stimulates a sequence of phosphorylation events mediated by RAF, MEK, and ERK (MAP) kinases

• activated MAP kinase (MAPK) translocates to the nucleus and activates proteins such as MYC, JUN, and FOS that promote the transcription of numerous genes involved in tumor growth

signaling via IGF-1 and IGF-2 and their receptor (IGF-1R) → phosphorylation and activation of oncogenic kinases in addition to activation of the EGFR pathway

central signaling pathway downstream of many receptor tyrosine kinases and regulates cell growth and proliferation

activating mutations in the gene encoding the p110 catalytic subunit of PI3K (PI3CKA) may be an important contributing factor to mammary

tumor progression PTEN dephosphorylates and inactivates PI3CKA — either

mutated or underexpressed in many breast cancers

PI3K/AKT PATHWAY

INSULINLIKE GROWTH FACTOR-1R

PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) PATHWAY• activated by RAS and by a number

of growth factor receptors (IGF1R and the ErbB1/ErbB2 heterodimer)

• activated PI3K generates phosphatidylinositol-3,4,5-triphosphate (PIP3), which activates phosphoinositide-dependent kinase-1 (PDK)

• PDK phosphorylates AKT• PTEN is an endogenous inhibitor of

AKT activation• phosphorylated AKT transduces

multiple downstream signals, including activation of the mammalian target of rapamycin (mTOR) and inhibition of the FOXO family of transcription factors

• mTOR activation promotes the synthesis of proteins required for cell growth and cell cycle progression

BREAST CANCER

Part 2: Clinical Practice

DEVITA CLUB

RISK FACTORS ↑ age (45 years and older), family history, exposure to female

reproductive hormones, dietary factors, benign breast disease, reproductive history, and environmental factors — small to moderate ↑ in risk

no identifiable risk factor — 50%

RELATIVE RISK <2 RELATIVE RISK 2–4

RELATIVE RISK >4

• Early menarche• Late menopause• Nulliparity• Estrogen plus

progesterone HRT• Alcohol use• Postmenopausal

obesity

• One first-degree relative with breast cancer

• CHEK2 mutation• Age >35 y for

first birth• Proliferative

breast disease• Mammographic

breast density

• BRCA1 or BRCA2 mutation

• LCIS• Atypical

hyperplasia• Radiation

exposure before 30

FAMILIAL/INHERITED FACTORS

true hereditary predisposition — 5% to 10% 1.5 to 3x ↑ risk if a woman has a mother or sister with

breast CA

BRCA1 AND BRCA2 MUTATIONS significant ↑ in the risk of breast and ovarian CA

breast CA — 26% to 85% ovarian CA — 16% to 63% (BRCA1) and 10% to 27%

(BRCA2) 5% to 10% of all breast cancers autosomal dominant inheritance with varying

penetrance BRCA1 or BRCA2 — associated with male breast CA,

fallopian tube CA, and prostate CA BRCA2 — also associated with melanoma and gastric

CA

FAMILIAL/INHERITED FACTORS

BRCA1 AND BRCA2 MUTATIONS BRCA1 histologic features

↑ incidence of medullary features ↑ proportion of grade 3 tumors ↓ proportion ER/PR expression infrequent HER2 overexpression triple-negative pattern — consistent with the

basal cell phenotype BRCA2 — not clear that the phenotype differs

from that seen in sporadic cancers, but some studies have suggested an ↑ of tubular and lobular carcinomas

FAMILIAL/INHERITED FACTORS

BRCA1 AND BRCA2 MUTATIONS

FACTORS SUGGESTIVE OF BRCA1 OR BRCA2 MUTATION

Non-Ashkenazic Jewish women• Two first-degree relatives with breast cancer, one diagnosed

≤50 years• Three or more first- or second-degree relatives with breast

cancer, any age• First-degree relative with bilateral breast cancer• Breast cancer in a male relative• Breast and ovarian cancer among first- and second-degree

relatives• Two or more first- or second-degree relatives with ovarian

cancerAshkenazic Jewish women• First-degree relative with breast or ovarian cancer• Two second-degree relatives with breast or ovarian cancer

HORMONAL FACTORSOVARIAN ACTIVITY total duration of exposure to endogenous estrogen —

important factor age-specific incidence of breast CA ↑ steeply with age

until menopause after menopause, the incidence continues to ↑ but the

rate of increase is ↓ to approximately 1/6 of that seen in the premenopausal period

oophorectomy before age 50 — markedly ↓ breast CA risk, with ↑ magnitude of risk reduction with earlier oophorectomy

age at menarche and establishment of regular ovulatory cycles — strongly linked to breast CA risk earlier age at menarche — ↑ risk

HORMONAL FACTORSPREGNANCY first full-term pregnancy after age 30 — 2 to 5x ↑

in risk compared to women with a first full-term pregnancy before approximately age 18

nulliparous women — 1.4x ↑ relative risk breast CA risk ↑ transiently (for approximately 10

years) after a pregnancy associated with a more durable protective effect may be due to:

↑ proliferation that precedes terminal differentiation before lactation

effect of ↑ levels of hormones on subclinical cancers

abortion — does not appear to ↑ breast CA risk breastfeeding (particularly for longer duration) — ↓ risk

of breast CA diagnosis

HORMONAL FACTORSCOMBINED ESTROGEN AND PROGESTIN HRT Women's Health Initiative study — HR of 1.24

noted after a relatively short duration of use ↑ abnormal mammograms after 1 year ↑ breast cancer incidence after 2 years

cancers occurring in HRT users — larger and more likely to have nodal or distant metastases, but of similar histology and grade

Million Women Study — RR of breast CA development of 1.66 and RR of breast CA death of 1.22

DIETARY/LIFESTYLE FACTORS

High-fat diets • ↑ Rates in observational studies• No association in a meta-analysis

High vegetable consumption

• May have a moderate protective effect

Fruit, fiber, and meat consumption

• Inconclusive

Alcohol • Linear ↑ in risk with the amount of alcohol consumed

Obesity • Positively correlated with plasma estrogen and estradiol levels

• ↑ Risk of breast CA development in postmenopausal women

• ↑ Breast CA mortality

BENIGN BREAST DISEASE

important predictor of breast CA risk

ionizing radiation — ↑ breast CA risk (particularly marked for exposure at a young age)

electromagnetic fields and organochlorine pesticides — suggested to ↑ breast CA risk, but evidence is lacking

Nonproliferative disease • Not associated with an ↑ risk of breast CA

Proliferative disease without atypia

• Small ↑ in risk (RR of 1.5 to 2.0)

Proliferative disease with atypical hyperplasia

• Greater risk (RR of 4.0 to 5.0)

Proliferative disease who have used estrogens

• No ↑ risk

BREAST DENSITY

ENVIRONMENTAL RISK FACTORS

MANAGEMENT OF THE HIGH-RISK PATIENT

high risk — no formal definition BRCA1 or BRCA2 mutations positive family history history of mantle irradiation LCIS or atypical hyperplasia

most significant risk factors family history age presence of a premalignant lesion on

previous breast biopsy

NSABP P1 prevention trial monthly breast self-examination, annual screening

mammography, and clinical breast examinations 1x or 2x yearly — does not clearly result in early detection in high-risk women

meta-analysis by Warner et al. — screening mammography vs. MRI in high-risk women (BRCA1/BRCA2) no mortality reduction with MRI screening of BRCA

mutation carriers, but the cancers detected in the MRI group were smaller and less likely to be associated with nodal positivity → possible survival benefit

American Cancer Society — recommended against the use of MRI screening for women with <15% risk of breast CA development

INTENSIVE SURVEILLANCE

tamoxifen and raloxifene — ↓ incidence of ER-positive breast CA

overview of 4 studies 38% ↓ in breast CA incidence 48% ↓ in the incidence of ER-positive breast cancers no effect on the incidence of ER-negative cancers RR of thromboembolic events — 1.9 RR of endometrial CA — 2.4

significant ↑ in endometrial CA and thromboembolic events was limited to postmenopausal women

most favorable risk-benefit ratio for tamoxifen premenopausal women younger postmenopausal women without a uterus atypical hyperplasia or LCIS

CHEMOPREVENTION WITH SERMs

NSABP P1 trial• 49% risk ↓ with

tamoxifen

  NSABP P2 trial[Study of Tamoxifen

and Raloxifene (STAR)]• no difference in the

incidence of invasive CA between women taking tamoxifen and those taking raloxifene (RR 1.02)

• more cases of noninvasive CA were noted in the raloxifene group (RR 1.40)

PROPHYLACTIC SURGERYBILATERAL MASTECTOMY retrospective review by Hartmann et al. — women with a

family history of breast CA 90% to 94% ↓ in breast CA incidence 81% to 100% ↓ in breast CA mortality

prospective study by Meijers-Heijboer et al. — BRCA mutation carriers no breast cancers in the prophylactic mastectomy group vs. 2.5%

per year incidence in those opting for surveillance

BILATERAL SALPINGO-OOPHORECTOMY added benefit of ↓ the risk of ovarian CA prospective study by Kauff et al. — BRCA mutation carriers

HR for breast CA ↓ to 0.32 meta-analysis by Rebbeck et al. — BRCA1 or BRCA2 mutation

carriers statistically significant ↓ in breast CA (HR 0.49)

DIAGNOSIS & BIOPSY MRI — sensitivity of 88.1% and specificity of

67.7% biopsy — standard technique

LOBULAR CARCINOMA IN SITU

risk of subsequent breast CA is bilateral 15% had invasive CA in the ipsilateral breast and 9.3% had

invasive CA in the contralateral breast ↑ rate of development of invasive CA of about 1% to 2% per

year, with a lifetime risk of 30% to 40% subsequent cancers are more often invasive ductal CA than

ILC most frequently diagnosed in women aged 40 to 50 (earlier

than DCIS) in the past, but recent literature indicates that the incidence in postmenopausal women is ↑

no specific associated clinical or mammographic abnormalities typically not associated with microcalcifications often an incidental, microscopic finding in a breast biopsy

performed for other indications

LOBULAR CARCINOMA IN SITU

both multifocal and bilateral in a large percentage of cases

typically positive for ER/PR staining and negative for HER2/neu staining

excisional biopsy generally recommended after detection of LN on

CNB to rule out coexisting DCIS or invasive CA most reported cases of malignant findings on

subsequent excision occur in the setting of either a suspicious mass lesion or calcifications that prompted the biopsy initially

not necessary to obtain negative margins of resection

no established role for RT

DUCTAL CARCINOMA IN SITU 15% to 30% of the cancers detected in mammography screening

programs greatest ↑ in the incidence of DCIS — women aged 49 to 69

years clinical presentation

palpable mass Paget disease of the nipple incidental finding at biopsy mammographically detected mass or calcifications —

most common presentation cancer-specific survival exceeds 95% appropriate therapy depends on:

extent of the DCIS lesion risk of local recurrence patient's attitude toward the risks and benefits of a particular

therapy

DUCTAL CARCINOMA IN SITUTOTAL/SIMPLE MASTECTOMY curative in approximately 98% primary medical indication — lesion too large

to be excised to negative margins with a cosmetically acceptable outcome

ACS/ACR/CAP recommendation — recommended for multicentric DCIS with: diffuse malignant calcifications in the breast negative margins cannot be obtained

DUCTAL CARCINOMA IN SITUEXCISION ALONE vs. EXCISION + RT localized DCIS

ACS/ACR/CAP recommendations: breast-conserving surgery + RT — recommended for localized DCIS

excised to clear margins boost — generally recommended, particularly for young patients

DUCTAL CARCINOMA IN SITUENDOCRINE THERAPY ER — present in about 80% of DCIS lesions 2 potential benefits

↓ in local recurrence after BCT prevention of the development of new primary

breast cancers in the contralateral breast tamoxifen

adds to the benefit of RT in ↓ ipsilateral events, but has little benefit in the absence of RT

substantially ↓ contralateral events in either case addition of tamoxifen to RT is particularly attractive in

young patients with ER-positive DCIS in whom the risk of local recurrence is higher and the toxicity of tamoxifen is less

LOCAL MANAGEMENT distant metastases at diagnosis — traditionally considered a

contraindication to surgery retrospective data have suggested a survival benefit for surgery of

the primary tumor in the patient presenting with metastatic disease, but systemic therapy remains the initial therapeutic approach

stage I and II — extensive evaluations for metastatic disease are not warranted in asymptomatic patients stage I — 0.5% incidence of metastases on bone scan and 0.1%

incidence on chest radiograph stage II — 2.4% incidence of metastases on bone scan and 0.2%

incidence on chest radiograph detection rate of occult metastases by CT/PET scans — ↓

stage III — occult metastases are more frequent (20%) → staging studies are recommended

T4 tumors and N2 disease — not candidates for surgery as the 1st therapeutic approach → initial systemic therapy

clinical stage I, II, and T3N1 disease — initial management is usually surgical

BREAST-CONSERVING THERAPY

goal — using conservative surgery (CS) and RT to provide survival equivalent to mastectomy with preservation of the cosmetic appearance and a ↓ rate of recurrence in the treated breast confirmed in the Milan I and NSABP B-06

trials lower rates of local recurrence — 10-year

actuarial rates of recurrence ranging from 2% to 7% in patients excised to negative margins

prolonged time course to local recurrence contrasted to those seen after mastectomy —

most local recurrences occur in the first 3 to 5 years

RISK FACTORS FOR LOCAL RECURRENCE

PATIENT RISK FACTORS patient age (<35 or 40)

consistently associated with ↑ risk of local recurrence after BCT ↑ frequency of adverse pathologic features such as lymphatic vessel

invasion, grade 3 histology, absence of ER/presence of HER2, and presence of an extensive intraductal component (EIC)

inherited susceptibility to breast and ovarian CA and other cancers (mainly BRCA1 and BRCA2) substantial risk of contralateral and late ipsilateral breast cancers

TUMOR RISK FACTORS margin of resection — most important tumor risk factor tumor size and nodal involvement — not prognostic factors for

local recurrence after BCT but are prognostic factors for distant recurrence

molecular subtype of the tumor — may be the significant determinant of both the likelihood and the time course of local recurrence after BCT and mastectomy

RISK FACTORS FOR LOCAL RECURRENCE

TREATMENT RISK FACTORS extent of breast resection use of a boost use of adjuvant hormonal therapy

NSABP B-14 trial — tamoxifen vs. placebo in node-negative, ER-positive patients after CS + RT 10-year rate of recurrence in the ipsilateral breast was 14.7% without

tamoxifen and only 4.3% with tamoxifen Stockholm Breast Cancer Study and NSABP B- 21 trial — similar

results use of adjuvant chemotherapy

sequential chemotherapy and RT — standard approach CT first — greater LOCAL recurrence RT first — greater DISTANT recurrence

NSABP B-13 trial — chemotherapy vs. no treatment in node-negative, ER-negative patients 8-year rate of recurrence in the ipsilateral breast was 13.4% without

chemotherapy and only 2.6% with chemotherapy given concurrently with the RT

BREAST-CONSERVING THERAPY

ABSOLUTE CONTRAINDICATIONS RELATIVE CONTRAINDICATIONS

Pregnancy• Absolute contraindication to the use of breast

irradiation• Possible to perform BCT in the 3rd trimester →

irradiation after delivery

Tumor size• Little published experience in treating patients

with tumor sizes >4 to 5 cm• Large tumor in a small breast — adequate

resection → significant cosmetic alteration

2 or more primary tumors in separate quadrantsDiffuse malignant-appearing microcalcifications

Breast size• Reproducibility of treatment by irradiation of

women with large or pendulous breasts

Prior therapeutic irradiation to the breast region• Requires retreatment to an excessively ↑ total

radiation dose to a significant volume

Collagen vascular disease (scleroderma or active SLE)• Poor tolerance to irradiation

Persistent positive margins• Warrant mastectomy• Single focally positive microscopic margin —

may not be an absolute contraindication

PREOPERATIVE SYSTEMIC THERAPY FOR OPERABLE CANCER

large tumor relative to the size of the breast not appropriate for patients with:

multicentric CA EIC that precludes a cosmetic resection preference for mastectomy

unicentric, higher-grade, ER-negative cancers — most likely to benefit from neoadjuvant chemotherapy

↑ clinical response rates and pathologic complete responses, but only 25% to 30% of patients who were not candidates for BCT at presentation were able to undergo the procedure after preoperative therapy (significantly ↓ total number of viable tumor cells, but viable tumor remains scattered throughout the same volume of breast tissue, precluding BCT)

meta-analysis of 9 randomized trials no ↑ or ↓ in survival with preoperative vs. postoperative

treatment ↑ risk of local-regional recurrence (RR 1.22)

PREOPERATIVE SYSTEMIC THERAPY FOR OPERABLE CANCER

HER2 overexpression — preoperative administration of trastuzumab + chemotherapy has been associated with ↑ rates of pathologic complete response (↑ from 26% to 65%) and significant improvement in disease-free survival, with no ↑ in cardiac dysfunction

neoadjuvant endocrine therapy — less experience with this approach than with chemotherapy preoperative use of an AI significantly ↑ the likelihood

of breast conservation in postmenopausal women with hormone-receptor-positive tumors higher response rate to letrozole was particularly likely in

patients with HER1/HER2 overexpression pathologic complete response is rare with the short

duration of treatment (3 to 4 months) used in the neoadjuvant setting

MANAGEMENT OF THE AXILLAAXILLARY DISSECTION standard approach to patients with axillary nodal

metastases regarded as a staging procedure that provided prognostic

information and maintained local control in the axilla NSABP B-04 trial — radical mastectomy vs. total

mastectomy + RT to regional lymphatics vs. total mastectomy + observation of axillary nodes and delayed axillary dissection if nodal metastases developed among clinically node-negative patients excellent long-term local control, with only 1.4% of

patients treated by radical mastectomy having an isolated axillary recurrence at 10-year follow-up

no survival benefit for the axillary surgery

MANAGEMENT OF THE AXILLASENTINEL NODE BIOPSY reliably identifies patients with axillary node involvement with a ↓

morbidity operation → allows axillary dissection to be limited to patients with nodal metastases who have the potential to benefit from the procedure

ACOSOG Z10 trial and NSABP B-32 trial — sentinel node could be identified in 98.6% and 97% of patients stage I and II — majority of patients are candidates accurate even in the presence of multicentric CA or a T3 primary tumor contraindications: 1) pregnancy, 2) lactation, and 3) locally

advanced breast CA NSABP B-27 trial — neoadjuvant chemotherapy → sentinel node

biopsy + axillary dissection 85% sentinel node identification rate and a false-negative rate of 11% —

similar to those observed in patients undergoing an initial sentinel node biopsy during the same time period

potential benefit of axillary downstaging and avoidance of axillary dissection

LOCAL-REGIONAL THERAPY AND SURVIVAL

3 HYPOTHESES CONCERNING THE BIOLOGY OF BREAST CANCER Halstedian theory

breast CA is strictly a local disease tumor cells spread over time in a contiguous manner by way of

lymphatics aggressive local-regional therapy would have a substantial impact

on survival → radical breast CA surgery systemic view by Bernard Fisher et al.

many breast CA patients developed distant metastases despite having locally controlled disease

if distant metastases were destined to develop, this had already occurred at the time of diagnosis → treatments that improved local-regional control would have little or no effect on overall survival

synthesis of aspects of these 2 opposing views for many breast cancers, there is a time when tumor cells have not

metastasized to distant sites, but it is generally not known whether this time has passed at the point of diagnosis

failure to achieve initial local control will allow some tumors to disseminate later to distant sites, reducing a patient's chance of long-term survival

LOCAL-REGIONAL THERAPY AND SURVIVAL

EBCTCG trial — more extensive vs. less extensive surgery, RT vs. no RT, and extensive surgery vs. RT improved local control at 5 years resulted in a highly

statistically significant improvement in both breast CA survival and overall survival at 15 years

addition of RT significantly improved 15-year absolute overall survival after breast conservation surgery by 5.3% and after mastectomy by 4.4% subset analysis: use of RT after mastectomy in node-

positive patients only improved 15-year survival in patients who also received adjuvant systemic therapy

survival benefits of achieving local-regional control are of similar magnitude to that for adjuvant systemic therapy

PROGNOSTIC AND PREDICTIVE FACTORS

PROGNOSTIC FACTORS PREDICTIVE FACTORS

• Stage• Extent of axillary lymph

node involvement — most established and reliable prognostic factor for subsequent metastatic disease and survival

• Tumor size • Histologic grading • Age • Involvement of

lymphovascular spaces

• ER/PR expression — most important and useful predictive factors, with some prognostic value

• HER2/neu gene

amplification — major predictive factor for benefit from trastuzumab, with some evidence that HER2 status is predictive for benefit from anthracycline-based chemotherapy

ADJUVANT TAMOXIFEN Early Breast Cancer Trialists' Group — overview of

the randomized trials of adjuvant tamoxifen therapy tamoxifen administered for 5 years results in a 41% ↓ in

the annual rate of recurrence (HR 0.59) and a 34% ↓ in the annual death rate (HR 0.66)

benefits are achieved independent of patient age or menopausal status, with and without the use of adjuvant chemotherapy, and are durable → improved survival through at least 15 years of follow-up

optimal duration — 5 years shorter durations are also beneficial, but appear to have

less impact extending tamoxifen therapy beyond 5 years in patients

with no evidence of tumor recurrence has not led to further improvements in disease-free or overall survival

ADJUVANT AROMATASE INHIBITORS profound estrogen depletion in postmenopausal women

only baseline levels of aromatase activity → AIs effectively ↓ estrogen levels

not appropriate for premenopausal patients — residual ovarian function can lead to enhanced production of aromatase

↓ risk of distant metastasis, in-breast recurrences and contralateral tumors → modest improvements in disease-free survival MA17 trial — addition of letrozole produced a statistically significant

survival benefit in the subset of node-positive women (HR 0.61) BIG 1-98 and TEAM study — equal rates of tumor recurrence with

either 5 years of an AI vs. 2 to 3 years of tamoxifen followed by 2 to 3 years of an AI for a total of 5 years of therapy

side effects accelerated osteoporosis — serial monitoring of bone mineral

density arthralgia syndrome

women with chemotherapy-induced amenorrhea — may have recovery of ovarian function

ADJUVANT CHEMOTHERAPY Oxford overview

benefit from chemotherapy irrespective of age, ER status, or whether patients also receive adjuvant endocrine therapy

advantages for multiple cycles (4 to 8) superiority of anthracycline-based chemotherapy vs. CMF-based

regimens multiple cycles of adjuvant chemotherapy, typically including

anthracycline-based regimens — recommended for the majority of patients with node-positive and higher risk node-negative tumors

Cancer and Leukemia Group B (CALGB) 9344 — doxorubicin dose escalation + sequential paclitaxel therapy for women receiving 4 cycles of AC chemotherapy sequential paclitaxel therapy improved both disease-free and

overall survival among women with node-positive breast CA other studies have failed to demonstrate that dose escalation of

cyclophosphamide or doxorubicin results in a lower risk of recurrence

ADJUVANT CHEMOTHERAPY randomized trial — AC → docetaxel or paclitaxel given either every 3

weeks or on a weekly schedule did not show significant differences between the taxanes with respect to

recurrence modest absolute advantages were seen with weekly paclitaxel and

every 3-week docetaxel neoadjuvant study — paclitaxel given weekly yielded superior rates of

pathologic complete response compared with every 3-week paclitaxel CALGB 9741 trial — AC → paclitaxel given either every 3 weeks or

every 2 weeks at the same doses; concurrent therapy vs. sequential chemotherapy accelerated, every 2-week treatment led to lower risk of recurrence and

improved survival no difference between concurrent or sequential therapy

CMF chemotherapy — equivalent to AC US Oncology trial — TC x 4 vs. AC x 4 in patients with node-negative or

one to three positive lymph nodes improvement in disease-free and overall survival with TC → option for

intermediate-risk patients

ADJUVANT CHEMOTHERAPY higher risk patients — unclear that anthracyclines can

be safely omitted NSABP B-30 — AC → T vs. TAC x 4 vs. doxorubicin/docetaxel x

4 in node-positive breast CA sequential AC → T was superior to TAC x 4, arguing by inference

that TC x 4 might not be sufficient considerations re: need for adjuvant chemotherapy

although the addition of chemotherapy often leads to statistically significant gains in relative risk reduction, these often translate into very small differences in the absolute risk of recurrence, esp. for patients with earlier stage disease or in patients where adjuvant endocrine therapy improves outcome

for patients in whom the absolute advantages of chemotherapy are modest, efforts to weigh patient preferences and directly quantify chemotherapy benefits for specific patients, as opposed to large cohorts in clinical trials, have led to further individualization of chemotherapy choices

ADJUVANT CHEMOTHERAPY hormone receptor status — may be an important

predictor of benefit from chemotherapy retrospective analyses among node-negative patients

— tumors that are ↓ or nonexpressors of ER derive substantial benefit from the addition of chemotherapy to tamoxifen, while tumors with ↑ quantitative levels of ER do not gain substantially from adding chemotherapy to endocrine therapy

retrospective review of CALGB trials for node-positive patients — improvements in outcome from changes in chemotherapy schedule and dosing, including the addition of taxane-based therapy, were most noticeable among patients with ER-negative tumors, while patients with ER-positive tumors derived more limited benefit from newer adjuvant chemotherapy regimens

ADJUVANT CHEMOTHERAPY HER2 — widely studied as a predictor of benefit

from adjuvant chemotherapy retrospective analyses — relative benefit from

anthracycline-based chemotherapy, and that HER2-negative tumors do not selectively benefit from anthracyclines, as opposed to CMF-type chemotherapy treatments

retrospective data — chemotherapy with taxanes may be esp. critical in tumors that either lack ER expression or express HER2

however, these chemotherapy trials all predate the widespread use of adjuvant trastuzumab, which may render moot the details of chemotherapy selection for HER2-positive tumors

ADJUVANT TRASTUZUMAB HER2 expression — adverse prognostic factor associated

with a higher and early risk of recurrence and relative resistance to established therapies such as CMF-based chemotherapy lower levels of hormone receptors than HER2-negative

tumors → relative resistance to adjuvant endocrine therapies significant improvements in DFS (average ↓ in risk of

50%) and in OS even after a short duration of follow-up cardiomyopathy — novel side effect

more pronounced in patients receiving anthracycline-based adjuvant chemotherapy (approx. 2%)

other risk factors: 1) pre-existing cardiac disease such as borderline normal LVEF or HPN and 2) age >65 years

all patients — baseline determination of LVEF and serial monitoring of cardiac function

ADJUVANT TRASTUZUMAB duration — 1 year

FinHER (Finland Herceptin) study — 9 weeks of trastuzumab + chemotherapy benefit for trastuzumab despite the short treatment exposure

HERA (Herceptin Adjuvant) trial — 1 year vs. 2 years of therapy NCCTG (North Central Cancer Treatment Group) N9831

trial — concurrent administration of trastuzumab during the taxane phase of treatment yielded superior results compared with sequential therapy

no data on whether trastuzumab would be effective as adjuvant treatment in the absence of chemotherapy

BCIRG 006 trial nonanthracycline trastuzumab/docetaxel/carboplatin (TCH) regimen

is superior to chemotherapy without trastuzumab anthracycline-based regimen followed by trastuzumab — lower risk

of recurrence (not powered to adequately compare TCH against the AC/TH treatment arms)

INTEGRATION OF MULTIMODALITY PRIMARY THERAPY

negative margins of resection — ↓ rates of local recurrence regardless of the sequence of RT and chemotherapy nonsignificant trend toward a greater risk of

distant recurrence in patients receiving RT first tamoxifen — should not be given concurrently

with chemotherapy randomized study — concurrent tamoxifen +

chemotherapy was associated with greater risk of recurrence

timing of surgery either before or after (neo)adjuvant chemotherapy —  does not alter long-term survival

FOLLOW-UP greatest risk of recurrence — first 5 years

still at risk for many years after treatment, esp. those who are hormone receptor-positive

screening for local recurrence after BCT and contralateral primary tumors — can be treated with curative intent regular breast examinations and annual mammography

distant metastatic disease — not clear that early detection contributes to substantial improvement in clinically important end points most distant recurrences are detected following patient-reported symptoms

such as bone discomfort, lymphadenopathy, chest wall/breast changes, or respiratory symptoms

asymptomatic detection through screening laboratory tests or radiology studies occurs in only a modest fraction of patients, even with intensive surveillance

2 randomized trials — vigorous surveillance with radiological imaging (CXR, bone scan, liver UTZ) and lab testing (CBC, LFTs, and serum tumor markers) vs. standard care (regular PE and mammography) more intensive surveillance achieved modest gains in early detection of metastasis,

with a small ↑ in the fraction of patients diagnosed while asymptomatic, but no improvement in overall survival

METASTATIC DISEASE most common sites — bone, lung, liver, lymph nodes, chest wall,

and brain hormone receptor-positive tumors — more likely to spread to

bone as the initial site of metastasis hormone receptor-negative and/or HER2-positive tumors —

more likely to recur initially in viscera lobular cancers — more often associated with serosal metastases

to the pleura and abdomen common symptoms or PE findings: bone discomfort,

lymphadenopathy, skin changes, cough or shortness of breath, and fatigue

tissue biopsy — imperative when radiologic or clinical findings are equivocal ER, PR, and HER2 should be redetermined

treatment goals: 1) prolongation of life, 2) control of tumor burden, 3) reduction in cancer-related symptoms or complications, and 4) maintenance of quality of life and function

ENDOCRINE THERAPY single-agent therapy — standard approach

combining endocrine agents has not been shown to improve outcomes

1st-line treatment — 8 to 12 months of tumor control 2nd-line treatment — 4 to 6 months of tumor control sequential single-agent 2nd- and 3rd-line endocrine treatments

— often effective, although typically for shorter durations than initial therapy

most women with hormone receptor-positive metastatic breast CA will eventually progress despite 1st-line endocrine therapy

indications for chemotherapy symptomatic tumor progression impending visceral crisis resistance to multiple endocrine therapies

induction chemotherapy followed by endocrine therapy — extensive visceral metastases or profound symptoms

CHEMOTHERAPY tumor response to chemotherapy — surrogate for longer cancer control and survival

1st-line treatment — higher response rates and longer tumor control than 2nd-line, and so forth

can be interrupted in patients who have had significant response or palliation following initiation of therapy and reintroduced when there is tumor progression or recrudescence of patient symptoms

combination chemotherapy may be associated with higher response rates and improved time to progression not shown to improve ultimate time to progression or survival compared with sequential

treatment may be required in patients with extensive visceral disease or impending visceral crisis

single-agent chemotherapy — preferred approach for most women better understanding of which drugs are contributing to benefit or side effects, allowing

appropriate treatment modification less toxicity

capecitabine — clinical activity in anthracycline- and taxane-resistant breast CA and improves response and survival as 1st-line treatment when added to single-agent docetaxel

gemcitabine — higher response rates and survival when paired with paclitaxel vs. paclitaxel therapy alone

ANTI-HER2 THERAPY trastuzumab — improved response rates, time to progression,

and overall survival generally started with chemotherapy, but may be considered

as single-agent therapy or in combination with endocrine therapy chemotherapy agents with clinical activity and safety when paired with

trastuzumab — taxanes, vinorelbine, and platinum analogs combination chemotherapy + trastuzumab — controversial continuation of trastuzumab treatment beyond progression —

improvements in time to progression lapatinib — dual-kinase inhibitor that targets both the HER2 and

EGFR tyrosine kinase signaling pathways 2nd-line anti-HER2 therapy for patients progressing after

chemotherapy + trastuzumab lapatinib + capecitabine — longer period of tumor control and

improvement in response rate but not survival vs. capecitabine chemotherapy alone

ER+ ER- HER2+

HER2- NODE+

NODE-

Anthracyclines ✔ ✔ ✔ (higher-

risk)

Taxanes ✔ ✔ ✔REGIMENS

Weekly paclitaxel, q3 weeks docetaxel

✪

ACT > TACx4 (> TCx4)

✪

TCx4 > ACx4 ✪(1-3

nodes)

✪

CMF = AC ✪ HER2+: Trastuzumab + taxane/vinorelbine/platinum agentsMETASTATIC DISEASE Anthracycline-/taxane-resistant: Capecitabine + docetaxel >

capecitabine Gemcitabine + paclitaxel > paclitaxel

OCCULT PRIMARY WITH AXILLARY METASTASES

uncommon — <1% initial evaluation: detailed history and PE, bilateral mammogram, ipsilateral breast

MRI (if the mammogram is unrevealing), and CXR MRI — identifies the primary tumor in the breast in a significant number of

patients with a normal mammogram and breast examination lymph node biopsy — ER, PR, or HER2 overexpression is strongly suggestive of

metastatic breast CA, although their absence does not exclude a primary breast tumor

mastectomy — based on the observation that approx. 50% of patients who do not receive therapy to the breast will develop clinically evident disease

whole-breast irradiation (50 Gy) — acceptable alternative to mastectomy axillary dissection — should be carried out regardless of the management

approach chosen for the breast because of the limited ability of radiation to control gross axillary disease

overall survival — similar to patients with comparable axillary involvement and a known primary tumor, but some investigators have suggested that survival is actually superior for those with occult primary tumors

systemic treatment — follows the current guidelines for patients with node-positive breast CA

BREAST CANCER AND PREGNANCY usually high-grade infiltrating ductal carcinomas characteristics and prognosis are generally similar to nonpregnant

women 1st or 2nd trimester — no clear evidence that pregnancy termination

changes overall survival mastectomy — can be safely performed during any trimester axillary dissection — standard management strategy RT — appropriate approach for cancers diagnosed in the 3rd trimester cytotoxic chemotherapy — risk of congenital malformation varies with the

fetal age and the agent used 1st trimester — 10% to 20% → AVOIDED 2nd and 3rd trimester — <2%

fluorouracil, doxorubicin, and cyclophosphamide — no complications taxanes — very limited experience, but to date fetal toxicity has not been

described trastuzumab — reversible anhydramnios methotrexate — abortion and severe fetal malformation tamoxifen — uncertain safety

growth retardation — may also occur

LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCERS (LABC AND IBC)

heterogeneous group of breast cancers without evidence of distant metastases (M0) operable disease at presentation (cT3N1) inoperable disease at presentation (cT4 and/or

N2-3) IBC (cT4dN0-3)

surgery — contraindicated unless there is complete resolution of the inflammatory skin changes

RT — may facilitate conversion of inoperable to operable disease

approx. 20% of patients treated with chemotherapy, surgery, and RT will experience local-regional recurrence → treated according to guidelines for metastatic breast CA

LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCERS (LABC AND IBC)

treatment — neoadjuvant chemotherapy, surgery, and RT induction chemotherapy (anthracycline- and taxane-based

regimens) vast majority of patients will have clinical response to therapy, and

roughly 15% to 25% will experience a complete pathologic response addition of paclitaxel to anthracycline-based therapy improves long-

term disease outcomes trastuzumab — incorporated into the treatment of women with HER2-

positive LABC or IBC postmastectomy RT — should be routinely done despite a

pathologic complete response to neoadjuvant chemotherapy due to higher risk of recurrence

BCT (limited experience) may be done in LABC except in patients with 1 or more of the

following features: 1) clinical N2-3 disease, 2) lymphovascular invasion, 3) residual primary pathologic size >2 cm, and 4) multifocal residual disease

contraindicated in women with IBC