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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