Metastatic/Recurrent Breast Cancer Flashcards
METASTATIC BREAST CANCER TREATMENT
Goals of therapy
Goals of therapy: palliation, prolongation of life (if possible) and to maximize quality of life; cure is
not likely (< 5% at 10 years); however, in some selected patients, disease may be controlled for many
years with good QOL.
METASTATIC BREAST CANCER TREATMENT
Response based on type
- Bone and Soft Tissue Mets: tend to have better prognosis and more likely to respond to endocrine
- Systemic visceral metastases generally require chemotherapy due to need for rapid response
- Brain mets: generally do not respond to chemo
HR receptor positive breast cancers tend to be more indolent and respond better to endocrine vs. HR-negative
- ER/PR or HER2 status can change w/ treatment and progression
METASTATIC BREAST CANCER TREATMENT
Olaparib
Biomarker
BRCA1/2 mutations
(germline sequencing)
Line of therapy:
ANY
METASTATIC BREAST CANCER TREATMENT
Talazoparib
Biomarker
BRCA1/2 mutations
(germline sequencing)
Line of therapy:
ANY
METASTATIC BREAST CANCER TREATMENT
Larotrectinib
Biomarker
NTRK fusion
Subsequent (after no
other satisfactory
alternative
treatments)
METASTATIC BREAST CANCER TREATMENT
Entrectinib
Biomarker
Subsequent (after no
other satisfactory
alternative
treatments)
METASTATIC BREAST CANCER TREATMENT
Pembrolizumab
Biomarker
MSI-H/dMMR
Tumor Mutational Burden High (TMB-H) defined as ≥
10 muts/mb
TNBC - PD-L1 expression
METASTATIC BREAST CANCER TREATMENT
Dostarlimab-gxly
Biomarker
Tumor Mutational BurdenHigh (TMB-H) defined as ≥
10 muts/mb
METASTATIC BREAST CANCER TREATMENT
Alpelisb + fulvestrant
Biomarker
Breast Cancer Subtype: HR-positive/HER2-negative
PIK3CA activating mutation
METASTATIC BREAST CANCER TREATMENT
Pembrolizumab +
chemotherapy (albumin bound paclitaxel,
paclitaxel, or gemcitabine +
carboplatin)
Biomarker
Breast Cancer Subtype: TNBC
PD-L1 expression using
22C3 antibody (threshold for positivity combined positive score (CPS) ≥ 10)
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
TARGETS
1) inhibit or eliminate production of estrogen:
- Oophorectomy or LHRH agonist (PREmenopausal)
- Aromatase Inihibitor (POSTmenopausal)
2) Block effect of estrogen at cellular level:
- Selective estrogen receptor modulators (SERMs) - PRE/POSTmenopausal
- Selective estrogen down regulators (SERDs) - POSTmenopausal
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
SERMS (pre and post menopausal)
PRE/POSTmenopausal
- Tamoxifen
- Toremifene: no advantage over tamoxifen, less data
Near complete cross resistance between SERMs
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
AI
- anastrazole
- letrozole
- exemestane
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
Selective Estrogen Receptor Down-regulators (SERDs)
Fulvestrant
- Approved for use in HR-positive, HER2-negative advanced breast cancer in postmenopausal women w/ disease progression following endocrine tx
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
LHRH agonists
- Leuprolide - not approved in US for breast cancer. Use in premenopausal pts only
- Goserelin - similar efficacy to leuprolide. Approved for advanced breast CA in US
- Triptorelin - Phase 2 trials indicate significant response in HR-positive pts as first line tx for metastatic BRCA
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
Sequencing
Sequential HT should be offered to patients with endocrine-responsive dx
No specific order of agents recommended
If patient responds to tx, predicts benefit to another agent
NCCN guidelines recommend chemo for patients with no clinical benefit after up to 3 sequential endocrine tx regimens
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
Combination vs. Sequential Single Agents
Sequential hormone therapy is preferred for most women with HR-positive MBC except in cases
of immediately life-threatening disease or those with rapid visceral recurrence during adjuvant
endocrine therapy
First line treatment with fulvestrant plus a non-steroidal AI may be offered as first-line
treatment
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
Premenopausal women
ASCO guidelines strongly recommend OAS in combination with treatment options as recommended for postmenopausal women
- tamoxifen or OAS alone (new pts)
Premenopausal women who develop metastatic disease while receiving adjuvant tamoxifen or within 12 months of treatment should be treated with OAS + AI.
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
NCCN Guidelines
HER2-Negative and Postmenopausal or
Premenopausal Receiving OAS
Preferred Regimens: 1st line
- CDK4/6 inhibitor + AI
- CDK4/6 inhibitor + fulvestrant
- SERD (fulvestrant) +/- non steroidal AI (anastrozole, letrozole)
METASTATIC BREAST CANCER TREATMENT
Endocrine Therapy
NCCN Guidelines
HER2-Positive and Postmenopausal or
Premenopausal Receiving OAS
- AI +/- trastuzumab
- AI +/- lapatinib
- AI +/- lapatinib + trastuzumab
- Fulvestrant +/- trastuzumab
- Tamoxifen +/- trastuzumab
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
When to consider Chemo Tx
Consider first-line chemotherapy for patients with:
a. ER/PR negative tumors
b. Symptomatic, visceral sites of metastases (visceral crises)
c. Faster growing; high ki-67
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Combination vs. sequential single agents
Sequential single agents are preferred, but chemotherapy combinations may be used in select
patients with high tumor burden, rapidly progressing disease, and visceral crisis
Combination regimens are generally associated with higher response rates compared to single agent chemo
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Combination vs. sequential single agents
A → T vs T → A vs AT (A = doxorubicin, T = paclitaxel).
Response rate and TTF (time to treatment failure) were higher with AT vs single agents
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Combination vs. sequential single agents
Docetaxel vs docetaxel + capecitabine
Response rates were higher with combination
TTP higher with combination
OS higher with combination
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Combination vs. sequential single agents
Paclitaxel vs paclitaxel + gemcitabine
Response rates higher in combination
OS higher in combination
Increased toxicity with combo
- Anemia
- Neutropenia
- Thrombocytopenia
- Neuropathy
- Fatigue
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Combination vs. sequential single agents
Paclitaxel vs paclitaxel + gemcitabine
Response rates higher in combination
OS higher in combination
Increased toxicity with combo
- Anemia
- Neutropenia
- Thrombocytopenia
- Neuropathy
- Fatigue
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Preferred Agents
- Doxorubicin/Doxil
- Paclitaxel
- Capecitabine
- Vinorelbine
- Gemcitabine
- Eribulin
- Cisplatin or Carboplatin
- Pembrolizumab + chemo (TNBC and PD-L1)
- Sacituzumab govitecan-hziy (TNBC)
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Anthracyclines
Doxorubicin vs Doxil
- Median PFS and OS similar between Doxil and Doxorubicin
Cross-resistance with anthracyclines
- Doxorubicin pretreated patients may respond to Doxil
- Conversions for calculating cumulative dose have not been established but Doxil appears to be LESS cardiotoxic
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Taxanes
Paclitaxel
Weekly schedules preferred
- greater efficacy
- better toxicity profile
- BUT less convenient
Side effects differ w/ weekly
- less myelopsuppression
- alopecia
- myalgias/athralgias
- peripheral neuropathy
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Taxanes
Docetaxel
Q3 week dose 60-100mg/m2
- increased response rates and TTP with higher doses
- similar median survival between doses groups
Side effects:
- neutropenia
- febrile neutropenia
- infection
- stomatitis
- diarrhea
- neurosensory
HIGHER toxicity with Q3wk vs Q1wk
Q1 week dose 30-35mg/m2
Incomplete cross resistance with paclitaxel
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Taxanes
Albumin-bound paclitaxel (nab-paclitaxel)
Response rates significantly better with albumin-bound paclitaxel every 3 weeks compared to paclitaxel q3wk
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Taxanes
Capecitabine
Approved as monotherapy for metastatic breast cancer resistant to paclitaxel and an anthracycline and in combination with docetaxel for metastatic breast cancer after failing an anthracycline-containing regimen.
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Taxanes
Platinum agents (CDDP, CARBO)
Preferred to taxane therapy for patients with germline BRCA mutations
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Sacituzumab govitecan
MOA
Mechanism of action: Trop-2-directed monoclonal antibody and topoisomerase inhibitor
conjugate. It consists of a humanized antibody attached to a small molecule, SN-38, which is a
topoisomerase I inhibitor.
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Sacituzumab govitecan
Indication
Indication: unresectable locally advanced or metastatic TNBC who have received two or more
prior systemic therapies, at least one of them for metastatic disease
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Sacituzumab govitecan
Toxicities
Common – neutropenia, nausea/vomiting (considered highly emetogenic), diarrhea,
constipation, fatigue, anemia, alopecia, rash, decreased appetite, abdominal pain
Severe
- Neutropenia (black box warning). Hold for ANC < 1500/mm3 or neutropenic fever.
Consider G-CSF for secondary prophylaxis.
- Diarrhea (black box warning) – administer atropine for early diarrhea of any severity.
Loperamide should be promptly initiated at the onset of late diarrhea.
- Anaphylactic reactions – premedicate with antipyretics, H1, and H2 blockers prior to
infusion. Corticosteroids may be used for patients who had prior infusion reactions.
Observation for at least 30 minutes following infusion is recommended.
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Ixabepilone
FDA approved indications:
Monotherapy for metastatic locally advanced BRCA after failure of anthracycline, taxane, capecitabine
In combo with capecitabine for the treatment of metastatic or locally advanced BRCA after failure of anthracycline and a taxane
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Ixabepilone
Toxicities
- Neutropenia (grade 3/4 50%);
- febrile neutropenia (rare);
- sensory neuropathy
(grade 3/4 15-20%); - fatigue; myalgias/arthralgias;
- infusion-related hypersensitivity reactions
(uncommon with premedications); combination has slightly more neutropenia, but similar capecitabine-related adverse events
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Eribulin
FDA Approved Indications:
Metastatic BRCA who have previously received ≥ 2 chemotherapeutic regimens
(prior therapies should include anthracycline and taxane)
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Eribulin
Adverse Events
- neutropenia
- neuropathy
- anemia
- alopecia
- asthenia/fatigue
- nausea
- constipation
- QT prolongation
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Vinorelbine
FDA approved indications:
Not FDA approved but has demonstrated activity
METASTATIC BREAST CANCER TREATMENT
Chemotherapy
Gemcitabine
FDA Approved Indications
Approved in combination with paclitaxel as first-line treatment of patients with metastatic breast
cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless
anthracyclines were clinically contraindicated
METASTATIC BREAST CANCER TREATMENT
Chemoimmunotherapy
Atezolizumab + albumin-bound paclitaxel
Indication has been WITHDRAWN (voluntarily)
METASTATIC BREAST CANCER TREATMENT
Chemoimmunotherapy
Pembrolizumab + chemotherapy
FDA approved indications
- Locally recurrent unresectable or metastatic TNBC who tumors express PD-L1 (CPS ≥
10) as determined by an FDA approved test
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
First Line Treatment
Trastuzumab
+
Pertuzumab
+
Taxane
(unless CHF or compromised LVEF)
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Second Line Treatment
- Ado-trastuzumab emtansine (T-DM1)
- Fam-trastuzumab deruxtecan-nxki
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Third Line Treatment
- Tucatinib + Trastuzumab + capcitabine
- preferred in patients with both systemic and CNS progression
- Trastuzumab + docetaxel or vino
- Trastuzumab + paclitaxel +/- carb
- Capecitabine + trastuzumab or lapatinib
- Trastuzumab + lapatinib
- Trastuzumab + other agents
- Neratinib + capecitabine
- Margetuximab-cmkb + chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine)
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Duration of Therapy
ASCO - at least 4-6 months or until maximum response, progression or unacceptable toxicities
NCCN - continue until progression or unacceptable toxicity
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
- ER+ and/or PR+
ASCO guidelines:
- HER2 targeted plus chemotherapy (Strong recommendation)
- Endocrine therapy + trastuzumab or lapatinib (in selected cases)
- Endocrine therapy alone (in selected cases)
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
TRASTUZUMAB
Activity in HER2+ MBC as single agent or in combination with chemotherapy
May be safely combined with all non-anthracycline regimens and single agents that are recommended for MBC
FISH Testing:
- IHC 3+ or FISH positive - significant predictor for response
- ICH 0-1 or FISH negative - No indication for trastuzumab
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
PERTUZUMAB
Addition of pertuzumab to docetaxel and trastuzumab improved PFS, OS compared to placebo
NCCN recommends combo of perjeta + trastuzumab in combo with taxane as preferred 1st line
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Adverse Events
- Diarrhea
- Rash
- mucosal inflammation
- febrile neutropenia
- dry skin
Pertuzumab discontinued if trastuzumab is discontinued
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Margetuximab-cmkb
MOA
HER2/neu receptor antagonist that binds to extracellular domain of HER2 and inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain, and mediates antibody-dependent cellular cytotoxicity
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Margetuximab-cmkb
Indication
In combination with chemotherapy for the treatment of adult patients with
metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2 regimens, at least
1 of which was for metastatic disease
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Margetuximab-cmkb
Adverse Events
Common:
- fatigue/asthenia
- nausea
- diarrhea
- vomiting
- constipation
- headache
- pyrexia,
- infusion-related reactions (all grade: 13%)
- alopecia
- decreased appetite
Severe:
- left ventricular dysfunction (1.9% of patients)
- febrile neutropenia,
- neutropenia/neutrophil count decrease
- infusion related-reactions (1.1%), - viral pneumonia and aspiration pneumonia
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Ado-trastuzumab emtansine (Kadcyla)
Indications
- NCCN Guidelines for HER2-positive MBC
- T-DM1 has also been evaluated as monotherapy vs. physician choice
(PFS - 6.2 mo vs. 3.3 mo) - CARDIOTOXIC
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Fam-trastuzumab deruxtecan-nxki (Enhertu)
Indications
- Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti Her2 based regimens in metastatic setting
DESTINY-03: New standard of care in the second line setting following trastuzumab + taxane
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Tucatinib (Tukysa)
MOA
Tyrosine Kinase inhibitor that inhibits HER2 and HER3 phosphorylation resulting in downstream inhibition of MAPK and AKT signaling and cell proliferation
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Tucatinib
Indications
Indications: In combination w/ trastuzumab and capecitabine for the treatment of adult patients w/ advanced unresectable or metastatic HER2+ breast cancer who have received >1 anti-HER2 based regimens
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Tucatinib
Toxicities
Common:
- diarrhea
- hand foot
- N/V
- fatigue
- anemia
- stomatitis
SEVERE:
- diarrhea
- Hepatotoxicity
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Neratinib + capecitabine
Indications
Received >=2 prior HER2-directed regimens for metastatic disease
METASTATIC BREAST CANCER TREATMENT
HER2 Targeted Therapy
Lapatinib (Tykerb)
Efficacy:
- Single agent w/ modest RR =24% for first line treatment and 8% for trastuzumab pretreated patients
- Longer PFS that received letrozole + lapatinib compared to letrozole
- Longer PFS in HER2+ patients that received trastuzumab + lapatinib compared to lapatinib alone
- Did not improve PFS or OS when added to fulvestrant in patients w/ ER+ MBC and increased toxicity
METASTATIC BREAST CANCER TREATMENT
CDK 4/6 Inhibitors
Drugs
- Palbociclib
- Ribociclib
- Abemaciclib
FDA: RARE Interstitial Lung Disease
METASTATIC BREAST CANCER TREATMENT
CDK 4/6 Inhibitors
Primary Use
Primary use in patients with HR+, HER2- advanced or metastatic breast cancer
METASTATIC BREAST CANCER TREATMENT
CDK 4/6 Inhibitors
PALBOCICLIB
Toxicity
CDK 4/6 Inhibitor
HR+, HER2- advanced
- Neutropenia
- Anemia
- Fatigue
FDA: RARE Interstitial Lung Disease
METASTATIC BREAST CANCER TREATMENT
CDK 4/6 Inhibitors
Ribociclib
Toxicity
CDK 4/6 Inhibitor
HR+, HER2- advanced
- Neutropenia
- LFT abnormality
FDA: RARE Interstitial Lung Disease
METASTATIC BREAST CANCER TREATMENT
CDK 4/6 Inhibitors
Abemaciclib
Toxicity
CDK 4/6 Inhibitor
HR+, HER2- advanced
- Diarrhea
- Neutropenia
- Nausea
- Fatigue
FDA: RARE Interstitial Lung Disease
METASTATIC BREAST CANCER TREATMENT
Everolimus
FDA Approved for combination with exemestane
- ER+
- HER2- MBC
- after failure of nonsteroidal AI
- Stomatitis
- Rash
- Diarrhea
- Hyperglycemia
METASTATIC BREAST CANCER TREATMENT
PARP Inhibitors
- olaparib
- talazoparib
Recurrent or Metastatic Breast Cancer for pts with germline BRCA1/2 Mutation
- Usually HER2-neg but can be used in ANY subtype
METASTATIC BREAST CANCER TREATMENT
Alpelisib
PIK3CA mutations
- HR+
- HER2-neg
Adverse Rxns
- hyperglycemia
- rash
