understanding and treating triple-negative breast cancer
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Understanding and Treating Triple-Negative Breast Cancer. Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA. Molecular Subtypes of Breast Cancer. Luminal A: ER+ and or PR+ Her2 -ve Luminal B: ER+ and or PR + Her2+ - PowerPoint PPT PresentationTRANSCRIPT
Understanding and Understanding and Treating Triple-Negative Treating Triple-Negative
Breast Cancer Breast Cancer
Elshami M. Elamin, MDElshami M. Elamin, MDMedical OncologistMedical Oncologist
Central Care Cancer CenterCentral Care Cancer Center
www.cccancer.com
Wichita, KS - USAWichita, KS - USA
Molecular Subtypes of Breast Cancer Molecular Subtypes of Breast Cancer
1.1. Luminal A: ER+ and or PR+ Her2 -veLuminal A: ER+ and or PR+ Her2 -ve
2.2. Luminal B: ER+ and or PR + Her2+Luminal B: ER+ and or PR + Her2+
3.3. Her2: Her2+ ER-ve PR-veHer2: Her2+ ER-ve PR-ve
4.4. Basal-like: ER-ve PR-ve Her2-ve, Basal-like: ER-ve PR-ve Her2-ve, cytokeratin 5/6+, and or Her1+cytokeratin 5/6+, and or Her1+
5.5. Normal-like: negative for all markersNormal-like: negative for all markers
Basal-like tumorsBasal-like tumors
Mostly ER/HER2–negativeMostly ER/HER2–negative
Marked increases in mitotic count, Marked increases in mitotic count, geographic necrosisgeographic necrosis
Pushing borders of invasionPushing borders of invasion
Stromal lymphocytic response Stromal lymphocytic response
BRCA1, BRAC2 Mutation CarrierBRCA1, BRAC2 Mutation Carrier
BRCA1:BRCA1:Chromosome 17Chromosome 17
57% risk of breast, 40% ov ca57% risk of breast, 40% ov ca
Bil breast caBil breast ca
ER-PR –veER-PR –ve
Higher GHigher G
Basal-likeBasal-like
BRCA 2:BRCA 2:Chromosome 13Chromosome 13
49% risk of breast, 18% ov ca 49% risk of breast, 18% ov ca
Pancreatic, prost, bile/GB, stomachPancreatic, prost, bile/GB, stomach
ER/PR +veER/PR +ve
BRCA 1-2:BRCA 1-2:2/3 - 3/5 of familial breast ca2/3 - 3/5 of familial breast ca
50-87% risk of invasive breast ca 50-87% risk of invasive breast ca
15- 65% risk of invasive epith ovarian ca15- 65% risk of invasive epith ovarian ca
EpidemiologyEpidemiology
In 2008, it is estimated that over 1 million In 2008, it is estimated that over 1 million women worldwide will be diagnosed with women worldwide will be diagnosed with breast cancer, of which breast cancer, of which 172,695172,695 will be will be classified as classified as ““triple-negative.triple-negative.
TNBCTNBCER/PR/ER/PR/Her2-neuHer2-neu negative negativeIt is characterized by:It is characterized by:
unique molecular profileunique molecular profilemajority carry the majority carry the ““basal-likebasal-like”” molecular profile on gene molecular profile on gene expression arraysexpression arrays majority of BRCA1-associated breast cancers are TN and majority of BRCA1-associated breast cancers are TN and basal-likebasal-likethe extent to which the BRCA1 pathway contributes to the the extent to which the BRCA1 pathway contributes to the behavior of sporadic basal-like breast cancers is an area of behavior of sporadic basal-like breast cancers is an area of active research active research
aggressive behavior aggressive behavior younger ageyounger agehigher mean tumor sizehigher mean tumor sizehigher-G higher-G higher rate of node positivity higher rate of node positivity
distinct patterns of metastasisdistinct patterns of metastasisEarly relapse Early relapse Predilection for visceral metastasis, including brainPredilection for visceral metastasis, including brain
lack of targeted therapieslack of targeted therapies
TNBCTNBC
Increasing evidence suggests that the risk Increasing evidence suggests that the risk factor profile differs between this subtype factor profile differs between this subtype and the more common luminal subtypes.and the more common luminal subtypes.
TNBCTNBC
Although sensitive to chemotherapy, early Although sensitive to chemotherapy, early relapse is common relapse is common
Targeted agents, (EGFR, VEGF, Targeted agents, (EGFR, VEGF, PARPPARP) ) inhibitors, are currently in clinical trials and inhibitors, are currently in clinical trials and hold promise in the treatment of this hold promise in the treatment of this aggressive diseaseaggressive disease
Relationship between TNBC, BRCA Relationship between TNBC, BRCA and Basal-like phenotypeand Basal-like phenotype
Triple-negative is a term based on clinical Triple-negative is a term based on clinical assays for ER, PR, and HER2assays for ER, PR, and HER2
Basal-like is a molecular phenotype initially Basal-like is a molecular phenotype initially defined using cDNA microarraysdefined using cDNA microarrays
characterized by low expression of ER, PR, and HER2 characterized by low expression of ER, PR, and HER2
Not all TNBC are basal-likeNot all TNBC are basal-like
Majority of BRCA1-associated breast cancers Majority of BRCA1-associated breast cancers are triple-negative and express a high proportion are triple-negative and express a high proportion of basal-like cytokeratins of basal-like cytokeratins
Current Treatment for Metastatic TNBC Current Treatment for Metastatic TNBC
No FDA-approved treatment No FDA-approved treatment option specifically for option specifically for metastatic TNBCmetastatic TNBC
Limited treatment options Limited treatment options for metastatic TNBCfor metastatic TNBC– Most patients already Most patients already
treated with adjuvant treated with adjuvant anthracycline, taxane, and anthracycline, taxane, and cyclophosphamidecyclophosphamide
– PFS ≤ 4 mos with PFS ≤ 4 mos with chemotherapy for chemotherapy for metastatic diseasemetastatic disease
Rationale for gemcitabine/ Rationale for gemcitabine/ carboplatin in MBCcarboplatin in MBC– Synergistic antitumor activity Synergistic antitumor activity
between gemcitabine and between gemcitabine and carboplatincarboplatin
– Active combination in MBC, Active combination in MBC, with response rates from with response rates from 21% to 53%21% to 53%
Rationale for PARP inhibitor– Rationale for PARP inhibitor– based therapy in TNBCbased therapy in TNBC– PARP1 is upregulated in PARP1 is upregulated in
majority of triple-negative majority of triple-negative human breast cancershuman breast cancers
1. Kassam F, et al. Clin Breast Cancer. 2009;9:29-33.2. Li HC, et al. Oncology (Williston Park). 2004;18(14 suppl 12):17-22.3. Loesch D, et al. Clin Breast Cancer. 2008;8:178-188.
Anthracycline/Taxane–Based Anthracycline/Taxane–Based
ChemotherapyChemotherapy
Two neoadjuvant studies:Two neoadjuvant studies:proportionally higher sensitivity to anthracycline- or proportionally higher sensitivity to anthracycline- or anthracycline/taxane–based chemo for basal-like/ER-anthracycline/taxane–based chemo for basal-like/ER-negative breast cancers compared to luminal/ER-positive negative breast cancers compared to luminal/ER-positive subtypes subtypes
Despite initial chemosensitivity, DFS (P = .04) and OS Despite initial chemosensitivity, DFS (P = .04) and OS ((P P = .02) remained poorest among those with basal-like and = .02) remained poorest among those with basal-like and HER2-positive tumors compared to luminal tumors HER2-positive tumors compared to luminal tumors
Pts with a pCR had excellent outcomes regardless of Pts with a pCR had excellent outcomes regardless of subtype subtype
the poorer outcome among triple-negative patients was the poorer outcome among triple-negative patients was attributed to a higher rate of recurrence among patients attributed to a higher rate of recurrence among patients with residual disease with residual disease
PlatinumPlatinum
Tumors with BRCA1 dysfunction harboring Tumors with BRCA1 dysfunction harboring deficient double-stranded DNA break repair deficient double-stranded DNA break repair mechanisms are sensitive to agents that cause mechanisms are sensitive to agents that cause DNA damage, such as platinum agents* DNA damage, such as platinum agents*
*Garber J, Richardson A, Harris L, et al: Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) (abstract 3074). Breast *Garber J, Richardson A, Harris L, et al: Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) (abstract 3074). Breast
Cancer Res Treat 100(suppl 1), 2006.Cancer Res Treat 100(suppl 1), 2006.*Sirohi B, Arnedos M, Popat S, et al: Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol June 20, 2008 (epub *Sirohi B, Arnedos M, Popat S, et al: Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol June 20, 2008 (epub ahead of print).ahead of print).*Yi S, Uhm J, Cho E, et al: Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinum-*Yi S, Uhm J, Cho E, et al: Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinum-containing chemotherapy (abstract 1008). J Clin Oncol 26(15S):43s, 2008.containing chemotherapy (abstract 1008). J Clin Oncol 26(15S):43s, 2008.
Targeted StrategiesTargeted Strategies
EGFR expression is seen in approximately EGFR expression is seen in approximately 60% of TNBC60% of TNBC
phase II trial (cetuximab + carbo):phase II trial (cetuximab + carbo): 18% RR, 27%% overall clinical benefit rate 18% RR, 27%% overall clinical benefit rate
CPT11/carbo +/- cetuximabCPT11/carbo +/- cetuximab49% vs 30% RR 49% vs 30% RR
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