Lecture 11 - Breast Cancer Flashcards
What is the #1 cancer in females
breast cancer
#2 in deaths in females
Lifetime risk of developing breast cancer
1 in 8 women
Reducing hormone replacement therapy has contributed to
a decrease in mortality of breast cancer
Risk factors
more than 60% of pts will NOT have any risk factors
increased age, family/personal history, radiation, estrogen exposure (early menarche and late menopause), exogenous estrogen (oral contraceptives/hormone replacement therapy), alcohol (decreased hepatic metabolism of estrogen), prior breast biopsies with proliferative history, nulliparity or age > 30 yrs old before first birth, elevated BMI (estrogen stores in adipose tissue), diet (soy/tofu are protective)
Genetics
only ~5-10% of breast cancers are familial
Genetics: tummor suppressor gene BRCA-1
increased risk of ovarian and breast cancers
Genetics: tummor suppressor gene BRCA-2
greater risk for breast cancer, lower risk for ovarian
greater incidence in male breast cancer
Types: invasive breast cancer
invasive carcinoma: has invaded beyond basement membrane of duct or lobule
invasive ductal carcinoma (most common), invasive lobular carcinoma (2nd most common)
Types: non-invasive
ductal carcinoma in situ
lobular carcinoma in situ
Ductal carcinoma in situ
normal cells have undergone pre-malignant genetic transformation; typically seen as microcalcifications on mammogram
Lobular carcinoma in situ
has not invaded beyond lobule basement membrane
Types: inflammatory
aggressive form of breast cancer with rapid onset and poor prognosis; onset typically days and weeks
pt present with edema, redness, warmth, inflammation, peau d’orange (orange peel look)
delayed in diagnosis bc most often thought of as cellulitis
FISH testing
can test for HER2 status in 2 different ways: immunohistochemistry - detects protein overexpression: 1+ (low tx group), 2+ (give FISH test), 3+ (give HER2 therapy); fluorescence in-situ hybridization: detects gene amplification
Prognostic tools: oncotype DX
genetic test for expression of 21 genes which gives a recurrence score; determines likelihood that breast cancer will return and whether the pt is likely to benefit from chemo
multi-gene assay validated for use in: newly diagnosed pts, stage I or II, lymph node (-) and (+), ER+, HER2(-)
Oncotype DX: TAILORx
low risk (<26) = hormonal therapy only
high risk (>/= 26) = chemo and hormonal therapy
however women < 50 with score of 16-25 did incur benefit from chemo
spares ~85% of people from getting chemo
General treatment strategies for stages I, II, and IIIA
goal is cure
breast conserving surgery: lumpectomy + XRT
modified radical masectomy
some pts have neoadjuvant chemo before surgery
most will receive adjuvant therapy after surgery
General treatment strategies for stages IIIB and IIIC
goal is cure
most women have neoadjuvant chemo followed by MRM or lumpectomy and XRT
adjuvant therapy as appropriate
General treatment strategies for stage IV
metastatic - treatment is palliative and primarily consists of chemo, hormonal therapy, +/- biologics, +/- immunotherapy
XRT may be used to palliate sx; surgery only for symptomatic relief
Neoadjuvant treatment
chemo, hormonal therapy, biologic therapy, immunotherapy
Adjuvant treatment
chemo, hormonal therapy, biologic therapy, immunotherapy, radiation
Metastatic treatment
chemo, hormonal therapy, biologic therapy, immunotherapy, radiation
Neoadjuvant therapy for stage I, IIA, IIB, III disease
goal of therapy is to achieve cure
neoadjuvant therapy: for pts with larger tumors (>1cm) - benefits: allows less extensive surgery, allows you to see response to chemo while tumor still intact
Systemic adjuvant therapy for stage I, IIA, IIB, III disease - hormone +, lymph node - and +, HER2 -
if tumor </-0.5 cm –> consider adjuvant endocrine therapy
if tumor > 0.5 cm or 1-3 positive nodes –> strongly consider 21 gene RT-PCR assay –> not done –> adjuvant endocrine therapy or chemo followed by endocrine therapy; if RS < 26 –> adjuvant endocrine therapy; if RS >/= 26 –> adjuvant chemo followed by adjuvant endocrine therapy
Systemic adjuvant therapy for stage I, IIA, IIB, III disease - hormone +, lymph node - and +, HER2 +
tumor </= 0.5 cm –> lymph positive or negative –> consider adjuvant endocrine therapy +/- chemo with HER2 targeted therapy
tumor > 0.6 –> lymph positive or negative –> adjuvant chemo with HER2 targeted therapy followed by endocrine therapy
Adjuvant hormonal therapy
surgical ablation
selective estrogen receptor modulators (SERMs)
LHRH analogs
aromatase inhibitors
Surgical ablation
oopherectomy: removes largest source of estrogen
only do in premenopausal women
SERMs
tamoxifen: anti-estrogenic effects in breast, but estrogenic properties in other tissues (bones, lipids)
used in pre and post-menopausal women
toxicities: hot flashes, endometrial cancer, DVT
LHRH analogs
leuprolide and goserelin
initially causes increased release of FSH and LH, but long-term sustained exposure inhibits LH and FSH –> inhibiting estrogen production by ovaries
used in pre-menopausal
Aromatase inhibitors
blocks androgens –> estrogens
use only in postmenopausal pts; need to use ovarian suppression (LHRH agonist) if in premenopausal
fewer AEs: no DVT/endometrial cancer, not protective effect on bone (like tamoxifen has); osteoporosis, hot flashes, muscle aches/pains
anastrozole, letrozole, exemestane
Premenopausal at diagnosis
tamoxifen x 5 yrs +/- ovarian suppression OR aromatase inhibitor x 5yrs + OS
Postmenopausal at diagnosis
aromatase inhibitor x 5 years than consider AI for additional 5 more years
Durations of adjuvant chemo longer than _____ do not appear to improve survival
3-6 months
Adjuvant chemo regimens - HER2 negative disease
dose dense doxorubicin and cyclophosphamide - repeat every 14 days x 4, (must give growth factors!) followed by paclitaxel
if there’s a risk of cardiotoxicity –> docetaxel and cyclophosphamide
Adjuvant HER2+ regimen
paclitaxel + trastuzumab (for people with more comorbidities or are older)
docetaxel, carboplatin, trastuzumab
docetaxel, carboplatin, trastuzumab, pertuzumab (harder to tolerate)
use trastuzumab for 1 year following chemo
Residual disease therapy
katherine trial: HER2+ with residual disease found on pathology after surgery - received ado-trastuzumab emtansine (TDM-1) or trastuzumab IV
TDM-1 = risk of recurrence of death was 50% lower compared to trastuzumab alone
if no residual disease, continue trastuzumab +/- pertuzumab x total 1 year
Triple negative breast cancer (TNBC): standard of care
now we incorporate immunotherapy into chemo regimen (ER/PR- and HER2-)
pembrolizumab should be added into chemo regimen and continues for 1 year
Triple negative disease
pembrolizumab + chemo: paclitaxel, carboplatin, pembrolizumab - complete 1 year of therapy
Metastatic disease
goal of therapy is palliation
symptomatic disease: chemo
bone/soft tissue metastases tend to have better prognosis and respond to hormonal therapy
Metastatic disease: ER/PR+, bone mets, asymptomatic visceral disease
–> hormone therapy –> endocrine therapy +/- bisphosphonate or denosumab if bone disease present
Metastatic disease: ER/PR-, symptomatic visceral disease, or hormone refactory
HER2+ –> anti-HER2 therapy +/- chemo –> anti-HER2 therapy +/- chemo
HER2- –> chemo –> chemo
Metastatic disease: how to decide what to give
hormonal therapy: ER/PR+, long disease-free survival, prior response to therapy, bone only disease
chemo: ER/PR-, short disease-free interval, rapidly progressing disease, disease refractive to hormonal therapy
Metastatic disease: single agent vs combo
combination therapy offers higher response rate but has more toxicities; few trials have demonstrated improved survival with combo chemo
Options for chemotherapy
single vs combination
TNBC
PD-L1 status
HER2+
BRCA status
Preferred single agent chemo - metastatic disease
doxorubicin, liposomal doxorubicin, paclitaxel, capecitabine, gemcitabine, vinorelbine, eribulin, sacituzumab govitecan-hziy
1st line option for HER2+ metastatic disease
trastuzumab + pertuzumab + docetaxel
trastuzumab + pertuzumab + paclitaxel
2nd line option for HER2+ metastatic disease
fam-trastuzumab deruxtecan-nxki
Fam-trastuzumab deruxtecan
HER2 low pts; don’t have to be HER2+ to get drug
1+ on IHC or 2+ on IHC and lacked gene amplification
interstitial lung disease SE!
Triple negative breast cancer in metastatic setting
platinum agents have shown benefit: carboplatin single agent - 1st line or cisplatin single agent - 1st line
pembrolizumab + chemo is better than chemo alone in pts with combined positive score of >/=10; if no positivity, then platinum-based chemo is preferred
Hormonal therapy in metastatic setting
HER2 negative and postmenopausal or premenopausal receiving ovarian suppression
1st line: aromatase inhibitor + CDK 4/6 inhibitor (abemaciclib, palbociclib, ribociclib)
2nd line: fulvestrant + CDK 4/6 inhibitor if not used before or everolimus + endocrine therapy (exemestane, fulvestrant, tamoxifen)
Cyclin dependent kinases
block conversion of G1 –> S phase
play an important role in drug resistance and its action can reverse some acquired resistance to previous hormone therapy
CDK 4/6 inhibitors
all approved in metastatic setting
abemaciclib, palbociclib, ribociclib
Breast cancer screening
self breast exams and clinical exams have been removed from the screening guidelines
breast self exam at age >/=20 years: discuss benefits and limitations
clinical breast exam: not recommended
mammogram: age 40-44: opportunity for annual exams, age 45-54: annual mammograms; age >/= 55 biennial mammograms
Breast cancer prevention
high-risk pts: discussion about risk reduction surgeries is warranted - BRCA mutations
prophylactic mastectomy can decrease risk by ~90%
bilateral oophorectomy can decrease estrogen exposure and decrease risk by ~50%
Prevention agents
tamoxifen and raloxifene
Tamoxifen prevention agent
decreased risk of invasive and noninvasive breast cancer in all women, decreased skeletal events, increased endometrial cancer, increased risk of stroke, PE and DVT
Raloxifene prevention agent
decreased incidence of breast cancer, as effective as tamoxifen, both reduced cancer by 50%
had fewer uterine cancer and blood clots; did not reduced risk of LCIS or DCIS like tamoxifen
