Breast Cancer Therapeutics

epidemiology

most common cancer in US 2024 (15%)
• 4th highest deaths (lung > colorectal > pancreatic > breast)

median age at diagnosis = 63

most present w/ local disease

5 year overall survival (OS) = 91%
• varies by stage (99% if stage I; 30% if stage IV) & type (triple negative breast cancer TNBC) → histology

men account for <1% of ALL cases

screening

US Preventative Services Task Force (USPSTF) (2024)
• ages 40-74 → mammogram every 2 years
• 40-49 previously individual risk/benefit

staging

stage I - breast ONLY

stage II - lymph nodes

stage III - further lymph nodes

stage IV - distant → liver, lungs, brain

initial workup

abnormal mammogram ± ultrasound
↓
biopsy - what type of breast cancer it is
↓
• HR+, HER2-
• HR+, HER2+
• HR-, HER2-

after initial workup, proceed to surgery or neoadjuvant therapy based on clinical findings, pathology &/or genetic testing

HER2 testing

immunohistochemistry (IHC)
• stain performed on tissue → HER2 protein presence
• scale: 0, 1+, 2+, 3+ → if 3+, no benefit for FISH test
• less sensitive, highly variable
• lower cost
*positive stain at B

fluorescent in situ hybridization (FISH)
• color changing DNA probes → HER2 DNA within cancer cells
• ratio of positive probes
• more sensitive, less variable
• higher cost
*red & green dots = (+) test at A

treatment options

surgery (stage I-III)

radiation (stage I-III)

systemic therapy (ALL stages)
• highly individualized based on tumor characteristics & risk factors

hormone therapy (ALL stages)
• HR+, following completion of chemotherapy (if applicable)

neoadjuvant* chemotherapy
*before surgery

gives advantage of knowing how cancer responds

usually chosen if
• T4 or N>1 based on clinical exam
• need to downsize tumor prior to surgery (lumpectomy desired?)
• need to treat sooner > waiting for recovery
• high risk (most common)/aggressive pathology based on biopsy (HER2+, triple negative breast cancer)

pembrolizumab + chemotherapy (Keynote-522)
• stage II/III TNBC, increased event free survival (EFS) & pathologic complete response (pCR)
• pembrolizumab + carboplatin/paclitaxel x4 cycles
• pembrolizumab + doxorubicin/cyclophosphamide (AC) x4 cycles
• surgery
• adjuvant pembrolizumab x9 cycles

adjuvant treatment

given to everyone else who do NOT get neoadjuvant

HR+, HER2-
HR+, HER2+
HR-, HER2- (triple negative)

adjuvant treatment: HR+, HER2-

endocrine therapy

preceded by chemotherapy (come before) IF
• primary >0.5 cm or node positive AND
• high risk by 21 gene assay (oncotype >26) → genetic testing

adjuvant treatment: HR+, HER2+

chemotherapy + trastuzumab > endocrine therapy

may NOT need chemotherapy + trastuzumab IF
• node negative AND
• primary ≤1 cm

maintenance w/ trastuzumab ± pertuzumab x1 year

*IF HR- but HER2+ = same pathways without use of endocrine therapy

adjuvant treatment: HR-, HER2+

chemotherapy + trastuzumab

may NOT need chemotherapy + trastuzumab IF
• node negative AND
• primary ≤1 cm

maintenance w/ trastuzumab ± pertuzumab x1 year

adjuvant treatment: HR-, HER2- (triple negative)

chemotherapy after (NOT before)

may NOT need IF
• node negative AND
• primary ≤1 cm

recurrent or stage IV breast cancer: locoregional recurrence

surgery ± radiation

consider systemic therapy
• pt specific risk/benefit discussion

*watch pt closely x5 yrs or longer

recurrent or stage IV breast cancer: HR+, HER2-

1st line
• aromatase inhibitor OR
• fulvestrant + CDK 4/6 inhibitor
• fulvestrant ± aromatase inhibitor

2nd line
• fulvestrant + CDK 4/6 inhibitor (if NOT previously used)
• additional lines of aromatase inhibitors, SERM, fulvestrant

chemotherapy

recurrent or stage IV breast cancer: HR+, HER2+

1st line
• aromatase inhibitor
• fulvestrant OR
• tamoxifen ± trastuzumab

other HER2-targeted agents

recurrent or stage IV breast cancer: HR-, HER2+

1st line - docetaxel (OR paclitaxel) + pertuzumab + trastuzumab

2nd line - fam-trastuzumab deruxtecan (preferred)

3rd line
• tucatinib/trastuzumab/capecitabine
• Ado-trastuzumab emtansine

trastuzumab + chemotherapy

recurrent or stage IV breast cancer: HR-, HER2- (triple negative)

PD-L1 ≥10% → chemotherapy + pembrolizumab (Keynote-355)
• paclitaxel, albumin-bound paclitaxel OR gemcitabine + carboplatin - 3 wk cycle

PD-L1 <10% → sequential single agent chemotherapy (NOT eligible)
• combination regimens IF large tumor burden, rapid progression, visceral crisis

*most aggressive & poorest outcome type → check for PD-L1 expression

recurrent or stage IV breast cancer: HER2-low?

DESTINY-Breast04 - established new treatment paradigm
• IHC +1 or +2 AND FISH negative
• fam-trastuzumab deruxtecan - 2nd line metastatic OR if recurrence during or within 6 months of adjuvant chemotherapy
• increased progression free survival (PFS) & overall survival vs. chemo alone

endocrine therapy in breast cancer: when to use

primary therapy for early stage low risk HR+

after completion of adjuvant chemotherapy in high risk or advanced HR+
• OR completion of primary chemotherapy for recurrent/stage IV HR+

in combination w/ targeted therapy for stage IV HR+

endocrine therapy in breast cancer: general monitoring & counseling

drug interactions (CYP2D6), adherence, side effects → #1 reason why pt is nonadherent

hot flashes
vasomotor symptoms
injection site pain (if IM)

endocrine therapy: 5 regimens

SERM → tamoxifen (premenopausal)
• duration: 5-10 yrs

3 aromatase inhibitors - anastrozole, letrozole, exemestane (post-menopausal)
• duration: 5-10 yrs

SERD → fulvestrant
• monthly IM injection

GnRH agonist → goserelin
• monthly SQ administered pellet

everolimus (mTOR inhibitor) + exemestane (if progressive disease on anastrozole or letrozole)

endocrine therapy: selective estrogen receptor modulator (SERM)

tamoxifen - competes w/ estrogen at cancer cell site
• used in premenopausal pts OR if unable to tolerate aromatase inhibitor
• duration: 5-10 years

endocrine therapy: aromatase inhibitors

anastrozole, letrozole, exemestane - equally effective
• blocks conversion of androgens to estrogens
• preferred in post-menopausal women OR in combination w/ ovarian suppression
• may cause more SE (myalgia, arthralgia)
• can switch between agents for tolerability/efficacy
• duration: 5-10 years

endocrine therapy: selective estrogen receptor degrader (SERD)

fulvestrant - monthly IM injection
• recurrent/stage IV alone OR in combination w/ targeted therapy (CDK 4/6 inhibitor) or aromatase inhibitor

endocrine therapy: GnRH agonist

goserelin - monthly SQ administered pellet
• ovarian suppression in combination w/ options for premenopausal women
*NOT directly treat cancer itself

endocrine therapy: everolimus + exemestane (if progressive disease on anastrozole or letrozole)

everolimus may help overcome resistance
• 56% w/ stomatitis → dexamethasone PO solution swish & spit x3-4 mo

chemotherapy

when to use
• neoadjuvant/adjuvant
• primary treatment IF stage IV HR-

general monitoring - myelosuppression, chemotherapy-induced N/V (CINV), bowel changes, neuropathy, echocardiogram

counseling - monitoring, antiemetic use, cardiotoxicity (anthracyclines)

chemotherapy: common regimens

dose dense AC (ddAC) (doxorubicin + cyclophosphamide) > paclitaxel → HER2- (may ADD trastuzumab IF HER2+)

TC = docetaxel + cyclophosphamide → HER2-

PTCH (pertuzumab/docetaxel/carboplatin/trastuzumab) > HP (trastuzumab + pertuzumab) → HER2+

single agent

chemotherapy: dose dense AC (ddAC) > paclitaxel

doxorubicin + cyclophosphamide every 2 weeks x4 cycles w/ granulocyte colony stimulating factor (GCSF) support

followed by 12 weeks of paclitaxel (weekly or dose dense) - usually 3-week dose q2wks

HER2-
• may ADD trastuzumab to paclitaxel if HER2+

chemotherapy: TC

docetaxel + cyclophosphamide every 3 weeks x4-6 cycles + granulocyte colony stimulating factor (GCSF)

HER2-, may use IF high risk genetics OR need to avoid cardiotoxicity

chemotherapy: PTCH > HP

pertuzumab, docetaxel, carboplatin, trastuzumab every 3 weeks x6 cycles + granulocyte colony stimulating factor (GCSF) - to maintain neutrophil count

followed by maintenance trastuzumab & pertuzumab to complete 1 year

HER2+ (early stage)

single agent chemotherapy

recurrent/metastatic disease when endocrine & targeted options are exhausted
• capecitabine - also used as adjuvant treatment AFTER neoadjuvant chemo for triple negative breast cancer
• conventional OR liposomal doxorubicin - cardiotoxicity, echo q3mo
• paclitaxel - neuropathy
• gemcitabine
• vinorelbine - neuropathy, constipation
• eribulin - neuropathy
• others

targeted therapies in breast cancer

HER2-directed (monoclonal antibodies) - trastuzumab, pertuzumab

HER2-directed (antibody drug conjugates) - ado-trastuzumab emtansine, fam-trastuzumab deruxtecan (Enhertu)

HER2-directed (PO) - lapatinib, neratinib, tucatinib

targeted therapy: HER2-directed (monoclonal antibodies)

trastuzumab (Herceptin, biosimilars 50%) 10-15% HER2+ = backbone
• neoadjuvant, adjuvant, recurrent/metastatic ± chemotherapy
• IV or SQ
• variable schedule: qweek or q3weeks

pertuzumab (Perjeta) - NEVER given by itself
• neoadjuvant, adjuvant, recurrent/metastatic + trastuzumab (synergistic!) & chemotherapy
• IV only
• q3weeks

pertuzumab, trastuzumab & hyaluronidase (Phesgo) - good absorption w/ small volume
• SQ - used in ANY regimen as substitute for IV trastuzumab + pertuzumab
• q3weeks = fixed dose

targeted therapy: HER2-directed (antibody drug conjugates)

ado-trastuzumab emtansine (Kadcyla)
• metastatic after progression on trastuzumab (H) ± pertuzumab (P), fam-trastuzumab
• adjuvant x1 year IF residual disease - better long-term outcome
➢ given in place of HP maintenance (trastuzumab & pertuzumab)
• q3weeks

fam-trastuzumab deruxtecan (Enhertu) - newest
• unresectable/metastatic after 1 or more HER2 treatment
➢ OR prior chemotherapy IF HER2-low
• superior to Kadcyla in 2nd line
• q3weeks

targeted therapy: HER2-directed (PO)

lapatinib (Tykerb) - rarely used
• after progression on trastuzumab (give w/ capecitabine)

neratinib (Nerlynx) - rarely used
• extended adjuvant therapy after trastuzumab OR w/ capecitabine after 2 prior HER2 treatment

BOTH w/ significant diarrhea risk, aggressive use of loperamide prophylaxis - minimal clinical benefit

tucatinib (Tukysa)
• unresectable/metastatic after 1 or more HER2 treatment in metastatic setting
• superior CNS penetration → BEST option if CNS metastasis
• must be given w/ trastuzumab & capecitabine

HER2-directed toxicities

cardiotoxicity (ALL) - monitor LVEF baseline & every 3 months

GI toxicity (ALL except trastuzumab) - diarrhea can be severe/dose limiting

conjugates (ado-trastuzumab, fam-trastuzumab) - chemo attached
• myelosuppression, esp. platelets & neutrophils
• N/V
• neuropathy w/ ado-trastuzumab
• interstitial lung disease/pneumonitis w/ fam-trastuzumab (6-16%)

CDK4/6 inhibitors

abemaciclib (Verzenio)
palbociclib (Ibrance)
ribociclib (Kiqali)

1st line IF recurrent or stage IV HR+, HER2- (w/ aromatase inhibitor or fulvestrant)

2nd line w/ fulvestrant IF no prior CDK4/6 inhibitor

adjuvant early stage (N+) high risk HR+/HER2- (abemaciclib + aromatase inhibitor + tamoxifen)

SE - neutropenia, diarrhea, interstitial lung disease (ILD)/pneumonitis

other targeted therapies

alpelisib (Piqray)

capivasertib (Truqap)

sacituzumab govitecan (Trodelvy)

PARP inhibitors - olaparib, talazoparib

other targeted therapies: alpelisib (Piqray)

advanced/metastatic: HR+, HER2-, PIK3CA+ mutation

2nd line or later after endocrine therapy (w/ fulvestrant)

SE - mucositis, diarrhea (→ prophylaxis), severe hyperglycemia (within days or wks), pneumonitis, dermatologic toxicities

other targeted therapies: capivasertib (Truqap)

advanced/metastatic: HR+, HER2-, PIK3CA/AKT1/PTEN alterations

2nd line or later after endocrine therapy (w/ fulvestrant)

modified dosing schedule (few days/wk) → lower incidence of SE

other targeted therapies: sacituzumab govitecan (Trodelvy)

trop-2 antibody drug conjugate; superior; days 1 & 8 q3wks

triple negative breast cancer (TNBC) after 2 prior therapies, at least 1 for metastatic disease

HR+ after endocrine therapy AND 2 prior therapies for metastatic disease

SE - myelosuppression, diarrhea, highly emetogenic, alopecia (GI toxicity!)

other targeted therapies: PARP* inhibitors
poly (ADP-ribose) polymerase

olaparib, talazoparib

adjuvant olaparib x1 year for HER2- w/ germline BRCA1/2
• alternative to KN522 (NOT routinely given w/ Keytruda)

metastatic HER2- w/ germline BRCA1/2 - olaparib OR talazoparib
• progression free survival (PFS) but NO overall survival benefit, improved quality of life (QoL)

SE - N/V, myelosuppression, 2ndary malignancies