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