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A Researcher’s Perspective: Myths and Facts    About Triple Negative Breast Cancer    Suzanne AW Fuqua, PhD and Julie Nang...
Breast Cancer Begins in Cells Within the Terminal Ducts                 =“Luminal”   =“Basal”                             ...
Breast Tumor Molecular Subtypes“Basal”= ER-        “Luminal”= Estrogen Receptor (ER)+        “HER2”+               Nature,...
Molecular Subtypes• Luminal: High expression of ER, the estrogen-regulated  progesterone receptor (PR), and cytokeratins 8...
Breast Cancer Subtype #1:       Luminal ER+
Growth Factor-ER Crosstalk is a Vicious Circle                           Proliferation Factor                           (C...
Cases           Julie Nangia, MD         Assistant Professor  Lester & Sue Smith Breast Center      Baylor College of Medi...
Pt LT: Initial Presentation• 74yo African American woman• Medical History  hypertension, hyperlipidemia, diabetes, heart d...
Pt LT: Diagnosis• Screening mammogram  Indeterminate calcifications left breast, new LNs    left axilla rec additional vie...
Pt LT: Examination & Staging• Exam  Breasts     • Right: no masses, skin or nipple changes     • Left: 5 x 5cm mass in the...
Pt LT: Treatment                                 Clinical Trial                               Anastrazole   Day 28        ...
Pt LT: Treatment• Randomized to anastrozole + fulvestrant    which she received for 140 days•   Left breast mass disappear...
Is ER a Useful Target? Yes Expression of ER predicts a better outcome Adjuvant therapy (treatment after surgery/radiatio...
Established Endocrine TherapyTwo pharmacological strategies•   Antiestrogens     Tamoxifen (NolvadexTM)     Fulvestrant   ...
Antiestrogen Therapy•   Reduces recurrence by 1/2, death by 1/3•   Benefit is continuing out to 15 years after 5 years of ...
Tamoxifen Saves LivesRecurrence                         Mortality             Lancet 2005, EBCTCG
The Future: Hormonal Therapy      + Targeted Therapy                                                                      ...
Breast Cancer Subtype #2:         HER2+
HER2 Targeted Therapy• Membrane protein overexpressed in 15-20% of breast cancers.• Before targeted therapy was associated...
Cases          Julie Nangia, MDPATIENT MB: HER2+ BREAST CANCER
Pt MB: Initial Presentation• 43yo woman• Past Medical History  none• Surgical History  none• Social History  No alcohol or...
Pt MB: Diagnosis• Pt felt a mass in her left breast• Diagnostic bilateral mammogram  3.5cm lobulated mass left breast at 1...
Pt MB: Examination & Staging• Examination  Breasts     • Right: No masses, skin or nipple changes.     • Left: 4 x 4cm mas...
Pt MB: Treatment  Lapatinib + Trastuzumab +/- Letrozole
Pt MB: Treatment• Placed on the study and received 12  weeks of traztuzumab + lapatnib• Left mastectomy  Pathologic Comple...
Why Dual HER2 Targeted Therapy is Better:The Cancer is “Addicted” to HER2 Stimulation!                            Dominant...
The Future: The Yin-Yang of HER-2 Targeted             Therapy With ER                                  IGFR              ...
Breast Cancer Subtype #3:Triple Negative (TN) = ER-/PR-/HER2-
Clinical Problem• ~25% of breast cancers are ER-negative.• Unfortunately, these patients are still being  treated with che...
Clinical Features of TN TumorsPatient char.            Younger age at diagnosis                         African origin    ...
Cases       Julie Nangia, MDPATIENT RO: METASTATIC TN      BREAST CANCER
Treatment of TN BC• No targeted therapy• Unless <1cm give chemotherapy containing an  anthracycline and taxane• Typical tr...
Pt RO: Initial Presentation• African American with a history of    breast cancer•   s/p right lumpectomy    • Infiltrating...
Pt RO: Recurrence• Goes to the hospital short of breath• CT chest  • Multiple bilateral pulmonary lung nodules  • Mediasti...
Pt RO: Treatment               No                                    GemcitabineMetastatic    prior                       ...
Pt RO: Treatment• Started on the BiPar study with  gemcitabine, carboplatin, and PARP  inhibitor• Was stable on this for 1...
New Hope: PARP Inhibitors• TN BC has clinical-pathological similarites with  BRCA-mutation bc which have a “broken” type o...
PARP Inhibitors: Preclinical Data Supported the Hypothesis But Clinical Data Does Not!       Unfortunately no significant ...
New Potential Targets in TN Cancers:               Ongoing Clinical Trials    •   BRCA+ (PARPi)    •   EGFR+ (Cetuximab, G...
Summary and Clinical ImplicationsThe Myth: TN breast cancer is defined by what is doesNOT have (ER-/PR-/HER2-)The Fact: We...
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A Researcher's Perspective: Myths & Facts about Triple Negative Breast Cancer - Dr. Suzanne Fuqua & Dr. Julie Nangia - 7th Annual Breast Health Summit

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Transcript of "A Researcher's Perspective: Myths & Facts about Triple Negative Breast Cancer - Dr. Suzanne Fuqua & Dr. Julie Nangia - 7th Annual Breast Health Summit "

  1. 1. A Researcher’s Perspective: Myths and Facts About Triple Negative Breast Cancer Suzanne AW Fuqua, PhD and Julie Nangia, M.D. Lester and Sue Smith Breast Center Baylor College of Medicine Houston, Tx sfuqua@bcm.edu; nangia@bcm.edu
  2. 2. Breast Cancer Begins in Cells Within the Terminal Ducts =“Luminal” =“Basal” From NIH Website
  3. 3. Breast Tumor Molecular Subtypes“Basal”= ER- “Luminal”= Estrogen Receptor (ER)+ “HER2”+ Nature, 2000, Perou et al.
  4. 4. Molecular Subtypes• Luminal: High expression of ER, the estrogen-regulated progesterone receptor (PR), and cytokeratins 8 and 18 (none overexpress HER2). Longest disease-free survival.• HER2: Overexpress this oncogene and other genes which are co-amplified with it. Some may also express low levels of ER.• Basal: Do not express ER or PR. Express cytokeratins 5, 6, and 17. Significantly shorter survival times. “Triple negative” is a subset of Basal (12-24% of all breast cancers) that does not express ER, PR, or HER2.
  5. 5. Breast Cancer Subtype #1: Luminal ER+
  6. 6. Growth Factor-ER Crosstalk is a Vicious Circle Proliferation Factor (Cells grow abnormally) ER HER2 Growth Survival Factor Factors (Keep cells from dying) (Blood)
  7. 7. Cases Julie Nangia, MD Assistant Professor Lester & Sue Smith Breast Center Baylor College of MedicinePatient LT: ER+ Breast Cancer
  8. 8. Pt LT: Initial Presentation• 74yo African American woman• Medical History hypertension, hyperlipidemia, diabetes, heart disease• Surgical History CABG, cholecystectomy• Social History No tobacco or alcohol, married, retired• Allergies none• Medications Pravastatin, toprol-XL, zestril, glyburide, metformin, norvasc, aspirin, actos• Family History No cancers
  9. 9. Pt LT: Diagnosis• Screening mammogram Indeterminate calcifications left breast, new LNs left axilla rec additional views/bx• Left diagnostic mammogram Heterogeneous calcifications in the inferior left breast, rec biopsy and US• Breast US Left Axilla Multiple enlarged LNs largest 2.7cm• Biopsy Left Axilla LN = metastatic carcinoma, ER 8/8, PR 2/8, Her2-
  10. 10. Pt LT: Examination & Staging• Exam Breasts • Right: no masses, skin or nipple changes • Left: 5 x 5cm mass in the upper outer quadrant • Lymph nodes: 2cm left axilla LN Otherwise exam was normal• Staging Work-up Bone scan • NED CXR • Nodular denisity left lower lung CT chest • NED, no nodules
  11. 11. Pt LT: Treatment Clinical Trial Anastrazole Day 28 Anastrazole Day 112 R AEligible N SURGERY Day 140Women Day 0 D Safety O Follow -Up M I Anastrazole Anastrazole Z Fulvestrant Day 28 Fulvestrant Day E (High dose) (High dose) 112 Breast core Breast core Surgical biopsy #1 biopsy #2 Specimen
  12. 12. Pt LT: Treatment• Randomized to anastrozole + fulvestrant which she received for 140 days• Left breast mass disappeared & left axilla LN was smaller• Left mastectomy No remaining invasive carcinoma 6/23 LN+ ER 5/8, PR 0, Her2-• Radiation therapy• Anastrzole (ArimidexTM) for total of 5 years
  13. 13. Is ER a Useful Target? Yes Expression of ER predicts a better outcome Adjuvant therapy (treatment after surgery/radiation) — 40-50% reduction in recurrence. Metastatic disease (treatment after recurrence) — 30-50% clinical benefit. However, incomplete cross-resistance can develop which necessitates sequential hormonal therapies.
  14. 14. Established Endocrine TherapyTwo pharmacological strategies• Antiestrogens Tamoxifen (NolvadexTM) Fulvestrant (FaslodexTM)• Aromatase inhibitors Anastrazole (ArimidexTM) Letrozole (FemaraTM) Exemestane (AromasinTM).
  15. 15. Antiestrogen Therapy• Reduces recurrence by 1/2, death by 1/3• Benefit is continuing out to 15 years after 5 years of tamoxifen• Tamoxifen blocks estrogen binding, but fulvestrant also causes ER loss• Fulvestrant has not proven better than tamoxifen, maybe due to poor metabolism.• Clinical trials now are evaluating higher doses of fulvestrant.
  16. 16. Tamoxifen Saves LivesRecurrence Mortality Lancet 2005, EBCTCG
  17. 17. The Future: Hormonal Therapy + Targeted Therapy X IGFR HER2 PI3 Kinase Cbl GRB2 SOS Ras p85 p110 Raf AKT MAPK MEK mTORp70SK6 pp90rsk Translation S6 P P X Basal ER ER CoA CBP Transcription Machinery DNA Proliferation
  18. 18. Breast Cancer Subtype #2: HER2+
  19. 19. HER2 Targeted Therapy• Membrane protein overexpressed in 15-20% of breast cancers.• Before targeted therapy was associated with poor prognosis.• Target with antibodies (trastuzumab/pertuzumab) and receptor enzyme inhibitors (lapatinib).• Clinical trials combining these +/- chemotherapy are underway. So far dual anti-HER2 therapy appears better.
  20. 20. Cases Julie Nangia, MDPATIENT MB: HER2+ BREAST CANCER
  21. 21. Pt MB: Initial Presentation• 43yo woman• Past Medical History none• Surgical History none• Social History No alcohol or tobacco, married• Family History No FH cancers• Allergies none• Medications none
  22. 22. Pt MB: Diagnosis• Pt felt a mass in her left breast• Diagnostic bilateral mammogram 3.5cm lobulated mass left breast at 12:00• Biopsy Infiltrating Ductal Carcinoma Grade 3 ER-, PR-, HER2+
  23. 23. Pt MB: Examination & Staging• Examination Breasts • Right: No masses, skin or nipple changes. • Left: 4 x 4cm mass superior of the nipple at 12:00 • Lymph Nodes: no axillary LN bilaterally• Staging Bone Scan • NED CXR • NED
  24. 24. Pt MB: Treatment Lapatinib + Trastuzumab +/- Letrozole
  25. 25. Pt MB: Treatment• Placed on the study and received 12 weeks of traztuzumab + lapatnib• Left mastectomy Pathologic Complete Response!!! No residual cancer in the breast 0/4 LN+
  26. 26. Why Dual HER2 Targeted Therapy is Better:The Cancer is “Addicted” to HER2 Stimulation! Dominant pathway Weakest pathway Escape pathway SignalingBCRT, 2011, Ahn and Vogel
  27. 27. The Future: The Yin-Yang of HER-2 Targeted Therapy With ER IGFR HER2 PI3 Kinase Cbl GRB2 SOS Ras p85 p110 Raf AKT MAPK MEK mTOR p70SK6 pp90rsk Translation S6 P P Basal ER ER CoA CBP Transcription Machinery DNA Proliferation
  28. 28. Breast Cancer Subtype #3:Triple Negative (TN) = ER-/PR-/HER2-
  29. 29. Clinical Problem• ~25% of breast cancers are ER-negative.• Unfortunately, these patients are still being treated with chemotherapy which does not cure all patients.• Goal is to identify molecular targets that control cancer cell growth.• At the Lester and Sue Smith Breast Center and Ben Taub clinic, we see 1200 patient visits; 120 new cases are TN.
  30. 30. Clinical Features of TN TumorsPatient char. Younger age at diagnosis African origin BRCA1 carrierTumor char. Ductal invasive cancer High grade Negative for ER, PR, HER2 Elevated mitotic count Tumor necrosis Pushing margin of invasion Larger tumor size Axillary nodal involvementTreatment/Prognosis Chemosensitive Few targets Poorer prognosis (trend to relapse first 3 yrs.) Aggressive relapse Cancer Treatment Reviews, 2010, Bosch et al.
  31. 31. Cases Julie Nangia, MDPATIENT RO: METASTATIC TN BREAST CANCER
  32. 32. Treatment of TN BC• No targeted therapy• Unless <1cm give chemotherapy containing an anthracycline and taxane• Typical treatment is 8 cycles of chemotherapy• No markers to predict prognosis• More likely to recur than other subtypes• If a patient has a pathologic CR they do better!
  33. 33. Pt RO: Initial Presentation• African American with a history of breast cancer• s/p right lumpectomy • Infiltrating ductal carcinoma 3.5cm • ER-, PR-, HER2- • 0/8 LN+• Received chemotherapy • AC x 4, Taxotere x 4• Received Radiation• Then 3 years later…
  34. 34. Pt RO: Recurrence• Goes to the hospital short of breath• CT chest • Multiple bilateral pulmonary lung nodules • Mediastinal LAD • Right pleural effusion• CT abdomen/pelvis • + bone involvement, no additional disease• Bone Scan • + bone involvement diffusely• Biopsy of lung nodule • Metastatic adenocarcinoma consistent with breast cancer
  35. 35. Pt RO: Treatment No GemcitabineMetastatic prior + Triple therapy Carboplatin Negative Randomized Breast Prior Gemcitabine Cancer Therapy + Carboplatin + BSI-201
  36. 36. Pt RO: Treatment• Started on the BiPar study with gemcitabine, carboplatin, and PARP inhibitor• Was stable on this for 1.5 years but then had to go off study because her low blood counts• Unfortunately she has recently progressed and is currently on another clinical trial
  37. 37. New Hope: PARP Inhibitors• TN BC has clinical-pathological similarites with BRCA-mutation bc which have a “broken” type of DNA repair.• PARP’s are a family of enzymes involved in DNA repair.• Hypothesis: preventing DNA repair via PARP inhibitors, in combination with the loss of DNA repair, will kill the tumor!
  38. 38. PARP Inhibitors: Preclinical Data Supported the Hypothesis But Clinical Data Does Not! Unfortunately no significant benefits of PARPi over chemotherapy alone to date Clinical Cancer Research, 2010, Anders et al.
  39. 39. New Potential Targets in TN Cancers: Ongoing Clinical Trials • BRCA+ (PARPi) • EGFR+ (Cetuximab, Gefitinib, Lapatinib) • AR+ (Casodex, Abiraterone Acetate) • SRC family of kinases+ (Dasatinib) • Nuclear receptors (Various antagonists)Funded by Susan G Komen for the Cure, Texas CPRIT, and Pharmaceutical Industry
  40. 40. Summary and Clinical ImplicationsThe Myth: TN breast cancer is defined by what is doesNOT have (ER-/PR-/HER2-)The Fact: We are defining TN by what it DOES have!New targeted therapies for TN BC will result fromfunded preclinical studies and your activeparticipation in clinical trials!Suzanne Fuqua, PhD Julie Nangia, M.D.
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