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| Massimo Cristofanilli, M.D., F.A.C.P. |
Triple-Negative Breast Cancer
• TNBC refers to a form of breast cancer which lacks
expression of ER, PR and HER2/neu
• It is estimated that 232,000 new cases of breast
cancer will be diagnosed in 2014
• Approximately 15-20% of breast cancers
• No targeted therapies currently approved for TNBC
–Iniparib (not a PARP inhibitor)
–Bevacizumab (VEGF inhibitor)
Risk factors for TNBC
• More common in young women and women of
African and Hispanic ancestry
• More common in women with a BRCA1 mutation
–75% with TNBC
• 15-20% of women with a BRCA2 mutation develop TNBC
• Patients with TNBC should consider genetic testing if
they have family history of breast/ovarian cancer or
are diagnosed at a young age
• More common in young women and women of
African and Hispanic ancestry
• More common in women with a BRCA1 mutation
–75% with TNBC
• 15-20% of women with a BRCA2 mutation develop TNBC
• Patients with TNBC should consider genetic testing if
they have family history of breast/ovarian cancer or
are diagnosed at a young age
Standard Treatments for Early-Stage TNBC
• Neoadjuvant/Adjuvant treatment
• Goal of therapy is curative
• Anthracycline and taxane-based chemotherapy
– Typically administered for 8 cycles (4 of each)
– Order doesn’t matter for adjuvant (T-(F)AC vs (F)AC-T)
– Anthracycline doesn’t matter (A vs E)
• Surgery
– Mastectomy vs Lumpectomy
• Radiation Therapy
– To breast and/or lymph nodes
• Neoadjuvant/Adjuvant treatment
• Goal of therapy is curative
• Anthracycline and taxane-based chemotherapy
– Typically administered for 8 cycles (4 of each)
– Order doesn’t matter for adjuvant (T-(F)AC vs (F)AC-T)
– Anthracycline doesn’t matter (A vs E)
• Surgery
– Mastectomy vs Lumpectomy
• Radiation Therapy
– To breast and/or lymph nodes
Recurrence Patterns of TNBC
• Most women with metastatic TNBC are first
diagnosed with early stage breast cancer
• Recurrences are most common within 3 years of
initial diagnosis
• Metastases are more common in
–Lungs, Liver, Brain
• Metastases are less common in
–Bone
• Most women with metastatic TNBC are first
diagnosed with early stage breast cancer
• Recurrences are most common within 3 years of
initial diagnosis
• Metastases are more common in
–Lungs, Liver, Brain
• Metastases are less common in
–Bone
Standard treatment for Metastatic TNBC
• Single-Agent Chemotherapy
– Taxanes
– Capecitabine
– Eribulin
– Liposomal doxorubicin
– Other microtubule inhibitors (ixabepilone, vinorelbine)
• Combination Chemotherapy Regimens
– Carboplatin+Gemcitabine
– Ixabepilone+Capecitabine
• Clinical Trials
• No targeted agents are currently approved for TNBC
• Single-Agent Chemotherapy
– Taxanes
– Capecitabine
– Eribulin
– Liposomal doxorubicin
– Other microtubule inhibitors (ixabepilone, vinorelbine)
• Combination Chemotherapy Regimens
– Carboplatin+Gemcitabine
– Ixabepilone+Capecitabine
• Clinical Trials
• No targeted agents are currently approved for TNBC
What we are learning about TNBC
• Research focused on TNBC is relatively recent
• TNBC is defined by characteristics it does not have
–ER/PR negative
–HER2 negative
• TNBCs are genetically unstable
–Chromosomes are actively rearranging
–Gene alterations are ongoing
–Treatments to target this instability are being developed
• There are different types of TNBC
*** If you have a recurrence, test for subtypes to
determine course of treatments.
• Research focused on TNBC is relatively recent
• TNBC is defined by characteristics it does not have
–ER/PR negative
–HER2 negative
• TNBCs are genetically unstable
–Chromosomes are actively rearranging
–Gene alterations are ongoing
–Treatments to target this instability are being developed
• There are different types of TNBC
*** If you have a recurrence, test for subtypes to
determine course of treatments.
What does this mean for those with TNBC?
• Being able to subdivide triple-negative breast
cancers into subcategories will help us identify
new targets for therapy
• Clinical research is ongoing to target pathways
that are implicated in TNBC and newer trials
are being developed based on this work
• Being able to subdivide triple-negative breast
cancers into subcategories will help us identify
new targets for therapy
• Clinical research is ongoing to target pathways
that are implicated in TNBC and newer trials
are being developed based on this work
Recent Clinical Trial Results
• Two randomized, phase II neoadjuvant trials presented at the
SABCS in December of 2013 demonstrated promising efficacy
for new treatments for early-stage TNBC
• Primary endpoint of study was to look at pathological
complete response rate (pCR)
• CALGB 40603
– T-AC
– +/- bevacizumab
– +/- carboplatin
• I-SPY2
– T-AC
– +/- carboplatin plus veliparib (ABT-888)
• Two randomized, phase II neoadjuvant trials presented at the
SABCS in December of 2013 demonstrated promising efficacy
for new treatments for early-stage TNBC
• Primary endpoint of study was to look at pathological
complete response rate (pCR)
• CALGB 40603
– T-AC
– +/- bevacizumab
– +/- carboplatin
• I-SPY2
– T-AC
– +/- carboplatin plus veliparib (ABT-888)
Summary of Results
• CALGB 40603
–Addition of bevacizumab lead to increased in breast pCR rates
but not in breast+axilla
–Addition of bev lead to an increase in serious toxicities
–Addition of carbo lead to significant increases in pCR rates in
breast and axilla, with increased but manageable toxicities
• I-SPY2
–TAC +/- (veliparib+carboplatin)
–Estimated pCR rate for veliparib+carbo predict a high likelihood
of success over control arm
–Veliparib/carbo arm associated with higher rates of hematologic toxicity
• CALGB 40603
–Addition of bevacizumab lead to increased in breast pCR rates
but not in breast+axilla
–Addition of bev lead to an increase in serious toxicities
–Addition of carbo lead to significant increases in pCR rates in
breast and axilla, with increased but manageable toxicities
• I-SPY2
–TAC +/- (veliparib+carboplatin)
–Estimated pCR rate for veliparib+carbo predict a high likelihood
of success over control arm
–Veliparib/carbo arm associated with higher rates of hematologic toxicity
Role of Carboplatin and Veliparib in TNBC
• Both CALBG 40603 and I-SPY2 suggest a role for carbo in the
management of a subset of TNBCs
• While carbo did increase risk of hematologic toxicities, these
toxicities were manageable (delays, dose mods)
• Addition of bev only seemed to increase in breast pCR rates,
but at the risk of life-threatening toxicities
• Contribution of veliparib is unclear
• A phase III study investigating the contribution of carbo and
carbo/veliparib for women with early stage breast cancer will
be opening soon
• A phase II neoadjuvant study is currently ongoing at TJU
• Both CALBG 40603 and I-SPY2 suggest a role for carbo in the
management of a subset of TNBCs
• While carbo did increase risk of hematologic toxicities, these
toxicities were manageable (delays, dose mods)
• Addition of bev only seemed to increase in breast pCR rates,
but at the risk of life-threatening toxicities
• Contribution of veliparib is unclear
• A phase III study investigating the contribution of carbo and
carbo/veliparib for women with early stage breast cancer will
be opening soon
• A phase II neoadjuvant study is currently ongoing at TJU
Targeted Therapies Currently Under Investigation for Advanced TNBC
• Immune therapy (PD-1/PD-L1 inhibitors) +/- chemotherapy
• Androgen receptor
• PARP inhibitors
– Mutation carriers (monotherapy)
– TNBC (in combination with chemo)
• GPNMB
• Glucocorticoid receptor
• AKT/PI3K/mTOR inhibitors
• Jak2 inhibitors
• Macrophages (the tumor microenvironment)
• Immune therapy (PD-1/PD-L1 inhibitors) +/- chemotherapy
• Androgen receptor
• PARP inhibitors
– Mutation carriers (monotherapy)
– TNBC (in combination with chemo)
• GPNMB
• Glucocorticoid receptor
• AKT/PI3K/mTOR inhibitors
• Jak2 inhibitors
• Macrophages (the tumor microenvironment)
Why has it been so hard to find a treatment?
• TNBC is not one disease
–It is important to understand which type of TNBC will
respond to which type of therapy
• Tumors are genetically unstable and are constantly
undergoing changes
• Newer technologies and clinical trials hold great
promise for the future
• TNBC is not one disease
–It is important to understand which type of TNBC will
respond to which type of therapy
• Tumors are genetically unstable and are constantly
undergoing changes
• Newer technologies and clinical trials hold great
promise for the future
Future Promise
• Much research is ongoing in the field of breast cancer
–Understand mechanisms of resistance
–Develop more personalized therapy
• New therapies are being developed and tested in
clinical trials specifically for TNBC
• Hope for the future
–More effective therapies
–Fewer side effects
• Much research is ongoing in the field of breast cancer
–Understand mechanisms of resistance
–Develop more personalized therapy
• New therapies are being developed and tested in
clinical trials specifically for TNBC
• Hope for the future
–More effective therapies
–Fewer side effects
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| Dr. Cristofanilli taking questions from the audience of mostly TNBC Survivors. Seated on the left is Arlene Brothers of the Triple Negative Breast Cancer Foundation |