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Medical Students 2011 - N. Pavlidis - BREAST CANCER SESSION - Systemic Treatment in Breast Cancer
 

Medical Students 2011 - N. Pavlidis - BREAST CANCER SESSION - Systemic Treatment in Breast Cancer

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  • Overexpression of the HER2 protein is a common molecular alteration in a number of human tumors. The overexpression is thought to result most frequently from the presence of multiple (i.e. more than 2) copies of the HER2/neu gene sequence ( gene amplification ) which are transcribed into multiple copies of RNA, and subsequently translated into abnormally high levels of the HER2 receptor protein ( protein over-expression ). HER2 protein density in tumor cells is 10- to 100-fold greater than in cells of the adjacent normal breast epithelium.
  • Primary objective of study: To determine whether adjuvant hormonal therapy (ie, experimental arm) is not inferior to adjuvant chemohormonal (standard arm) for patients in the “primary study group” (Oncotype DX RS 11-25)

Medical Students 2011 - N. Pavlidis - BREAST CANCER SESSION - Systemic Treatment in Breast Cancer Medical Students 2011 - N. Pavlidis - BREAST CANCER SESSION - Systemic Treatment in Breast Cancer Presentation Transcript

  • SYSTEMIC TREATMENT IN BREAST CANCER N. PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF IOANNINA GREECE ESO COURSE IOANNINA, JULY 2011
  • SYSTEMIC TREATMENT OF BREAST CANCER
    • CHEMOTHERAPY
    • HORMONAL THERAPY
    • TARGETED THERAPY
    • BISPHOSPHONATES
  • SYSTEMIC TREATMENT OF BREAST CANCER
    • Can be provided as:
      • NEOADJUVANT THERAPY
    • Preoperatively
      • ADJUVANT THERAPY
    • Postoperatively
      • THERAPY FOR METASTATIC DISEASE
  • SYSTEMIC TREATMENTS
    • NEOADJUVANT SYSTEMIC THERAPY [Preoperatively]
    •  To make non-operable tumors operable
    •  To achieve breast conservation
    •  To select sensitivity for specific treatment (biomarkers)
    • ADJUVANT SYSTEMIC THERAPY [Postoperatively]
    •  To kill micrometastatic disease
    •  To increase disease – free survival
    • THERAPY FOR METASTATIC DISEASE
    •  Palliative intent (symptoms control)
    •  To prolong survival
    Rationale: Rationale: Rationale:
    • THE INTENTIONS
    • Neoadjuvant / Adjuvant Rx  TO CURE (?)
    • Rx for Metastatic Disease  TO PALLIATE
    • TO EXTEND SURVIVAL
  • CHEMOTHERAPY IN BREAST CANCER
  • ACTIVITY OF CYTOTOXIC DRUGS IN BREAST CANCER
    • VERY ACTIVE (  50% RR)
    • Docetaxel
    • Doxorubicin
    • Epirubicin
    • Liposomal doxorubicin
    • Paclitaxel
    • Vinorelbine
    MODERATELY ACTIVE (20-50% RR) Cisplatin / Carboplatin Cyclophosphamide Fluorouracil Methotrexate Mitomycin – C Mitoxantrone Vinblastine Vincristine Capecitabine Gemcitabine Ixabepilone COMMON COMBINATION IN USE : CMF, CNF, FAC, AC, AT
  • HORMONAL THERAPY IN BREAST CANCER
  • ENDOCRINE THERAPIES IN ADVANCED BREAST CANCER TREATMENTS EFFECTS ON ESTROGENS SERMs (Selective Estrogen,Receptor Modulators) Tamoxifen Toremifene Raloxifene Occupy estrogen receptors ERD (Estogen Receptor, Down regulators) Fulvestrant Reduce expression of estrogen receptor, progesterone receptor and proliferative and cell turnover PROGESTINS Occupy progesterone receptors (reducing estrogen receptors and estrogen action)
  • ENDOCRINE THERAPIES IN ADVANCED BREAST CANCER TREATMENTS EFFECTS ON ESTROGENS AROMATASE INHIBITORS Anastrazole Letrozole Exemestane
    • Interfere with aromatase which converts androstendione to estrone and then to estradiol (reducing estrogen levels)
    • For postmenopausal pts
    GnRH ANALOGUES Goserelin Triptorelin
    • Inhibit gonadotrophin release from the pituitary (reduced estrogen levels)
    • For premenopausal pts
  • TARGETED THERAPY IN BREAST CANCER
  • EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR
    • Human breast carcinomas frequently co-express the EGF receptor and the other 3 members of the EGF receptor family (HER 2, - 3 and – 4).
    • These receptors are composed of an extra-cellular binding domain, a transmembrane lipophilic segment and an intracellular protein tyrosine kinase domain with a regulatory carboxyl terminal segment.
    • Overexpression of EGFR has been found in human breast cancer along with its ligands, suggesting a possible autocrine loop.
  • NORMAL CELL BREAST CANCER CELL gene amplification and overexpression of HER2 protein (10-fold to 100-fold) HER2 HER2 gene HER2 protein HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2
  • Herceptin ® (trastuzumab) – humanised anti-HER2 antibody
    • Targets HER2 oncoprotein
    • High affinity (K d =0.1 nM) and specificity
    • 95% human, 5% murine
      • decrease potential for immunogenicity
      • increase potential for recruiting immune-effector mechanisms
  • BISPHOSPHONATES IN BREAST CANCER
  • BISPHOSPHONATE THERAPY
    • Pamidronate 90 mg iv every 3-4 weeks over 2 hours
    • Zoledronate 4 mg iv every 3-4 weeks over 15 min
    • Clodronate 1600 mg/d p.o.
  • MODE OF ACTION
    • BISPHOSPHONATES
    • Inhibit osteoclast activity and alter the signaling between tumor and bone
  • B I S P H O S P H O N A T E S
    • Reduction of skeletal complications
    • Treatment of hypercalcemia
    • Reduction of incidence of hypercalcemia
    • Prevention of skeletal metastases
    • Reduction in tumor burden
    • Improvement in overall survival
  • NEOADJUVANT CHEMOTHERAPY IN BREAST CANCER
    • MAIN INDICATIONS : i) STAGE III A-B or T 3-4
    • ii) Inflammatory breast cancer
    • iii) Involvement of ispilateral supra- or infraclavicular LNs
    • SECONDARY INDICATIONS : i) Desire for breast –conservation after biopsy or lumpectomy
    • ii) Medical contraindications to surgery
    • iii) Pregnant women with breast cancer (> 2 nd trimester)
    • RECOMMENDED REGIMENS: i) Anthracycline – based chemotherapy
    • (x 4 cycles)
    • ii) Taxanes or trastuzumab (look promise but need further investigation)
  • All Breast Cancer ER + 65-75% Triple neg 15% HER 2+ 15-20% BREAST CANCER IS NOT ONE OF A KIND !
  •  
  •  
  • BREAST CANCERS IN YOUNG WOMEN WHAT IS DIFFERENT ?
    • Clinical and biologic variables make breast cancer in young women at poorer prognosis compared to less young women !
  • BREAST CANCERS IN YOUNG WOMEN ARE LARGER - WHAT ELSE ?
  • TRIPLE NEGATIVE BREAST CANCER IS MORE COMMON IN YOUNG WOMEN PATIENTS
  • BREAST CANCERS IN YOUNG WOMEN WHAT IS DIFFERENT ?
  • BREAST CANCERS IN YOUNG WOMEN WHAT IS DIFFERENT ?
  • ADJUVANT SYSTEMIC TREATMENT IN BREAST CANCER (ESMO CLINICAL RECOMMENDATIONS)
  • ADJUVANT SYSTEMIC TREATMENT IN BREAST CANCER
    • PROGNOSTIC FACTORS
    • MAIN
    • Axillary lymph node involvement
    • Tumor size
    • Grade of differentiation
    • Age
    • Estrogen and Progesterone receptors (ER or PR)
    • Peritumoral vascular invasion
    • c- erb 2 (HER2 / neu)
    • OPTIONAL
    • p 53
    • Cathepsin –D
    • others
  • RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER Low risk Node-negative and all of the following features Estimated risk of recurrence in 10 years (%) pT ≤ 2 cm Grade 1 Absence of extensive peritumoral vascular invasion ER and /or PgR expressed HER2 gene neither overexpressed nor amplified Age ≥ 35 years < 10
  • RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER Intermediate risk Node-negative and at least one of the following features Estimated risk of recurrence in 10 years (%) pT > 2 cm Grade 2-3 Presence of extensive peritumoral vascular invasion ER and PgR expressed HER2 gene overexpressed or amplified Age ≥ 35 years < 10 Node - positive (1-3 involved nodes) AND ER and/or PgR expressed AND HER2 gene overexpressed or amplified 10 - 50
  • RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER High risk Node-positive (1-3 involved nodes) AND Estimated risk of recurrence in 10 years (%) ER and PgR absent OR HER2 gene overexpressed or amplified Node-positive (4 or more involved nodes) < 50
  •  
  • ADJUVANT CHEMOTHERAPY Recurrence < 50 Breast Cancer Mortality 50-69 EBCTCG, Sept 2006 On average, chemotherapy is good for you
  • TRASTUZUMAB IN ADJUVANT SETTING WHERE DO WE STAND TODAY ?
  • Summary of Trastuzumab Adjuvant Trials Study FU, yrs Pts HERA 1 3,387 2 3,401 NSABP B-31/ NCCTG 9831 2 3,351 4 3,968 NCCTG 9831 seq BCIRG 006 1.5 3 1,964 3,222 FinHer 3 231 PACS 04 4 528 0 1 2 In favor of T In favor of Obs. HR 0.54 0.64 0.48 0.48 0.87 0.61 0.42 0.86
  • The future …. Looking at the biological target
  • Sorlie, T et al: PNAS 2001; 98:10869-10874 Breast Cancer is a Heterogeneous Group of Diseases OS DFS
  • MOLECULAR CLASSIFICATION AND TREATMENT OF BREAST CANCER TYPE CHARACTERISTICS TREATMENT Luminal A ER+/PR+/HER-/GR I (Ki67 < 14%) Endocr Rx alone Luminal B ER+/PR+/HER-/GR III (Ki67 high) Chemo+Endocr Rx ER+/PR+/HER+/GR any Chemo+anti-HER2+Endocr Rx HER-2 overexpression HER (+), ER- PR Chemo+anti-HER2 Rx Basal-Like Triple negative Chemo Rx
  • Genomic Profile Determine Which Patients Receive Adjuvant Chemotherapy ?
    • The Panel accepts molecular - based tools ( such as the 21-gene recurrence score assay ) or gene expression profiling ( such as by the 70-gene assay ) as an adjunct to high-quality standard histopathologic assessment to refine risk categories.
    • The Panel recognizes in many cases this may provide more optimal individual risk allocation for making a decision to add chemotherapy or not .
  • Oncotype DX 21 Gene Recurrence Score (RS) Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies Category RS (0 – 100) Low risk RS < 18 Int risk RS ≥ 18 and < 31 High risk RS ≥ 31 RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1
  • TAILORx Node Neg, ER (+), Breast Cancer RS < 10 Hormone Therapy Registry RS 11 – 25 Randomize Hormone Rx vs. Chemotherapy + Hormone Rx RS > 26 Chemotherapy + Hormone Rx Onco type DX Assay Register Specimen banking Primary study group
  • SYSTEMIC TREATMENT FOR METASTATIC DISEASE
  • C H E M O T H E R A P Y IN METASTATIC BREAST CANCER
  • ORGAN PREDILECTION FOR DISTANT METASTASES IN BREAST CANCER SITE PERCENTAGE (%) Lymph nodes 74 Thorax Lung Pleura Pericardium Heart 64 37 22 11 Abdomen Liver Adrenals Spleen Intestine Peritoneum Ovaries Uterus Kidney Pancreas 60 40 18 18 17 15 15 15 14 Bones 57 Skin 35 Brain 15
  • FACTORS AFFECTING PROGNOSIS IN METASTATIC BREAST CANCER FAVOURABLE UNFAVOURABLE ER/PR positive tumour ER/PR negative tumour Long disease free interval (> 2 years) Short disease free interval (< 1 year) Response to first line therapy No response to first line therapy No visceral involvement Visceral involvement Limited metastatic sites, no bulky disease Multiple metastatic sites and/or bulky disease HER-2 negative tumour HER-2 positive tumour
  • SYSTEMIC MANAGEMENT OF METASTATIC BREAST CANCER ACCORDING TO RISK SUBSETS RISK EVALUATION FAVORABLE SUBSETS UNFAVORABLE SUBSETS ENDOCRINE THERAPY CHEMOTHERAPY
  • COMBINED SYSTEMIC TREATMENT IN ABC A HISTORICAL OVERVIEW DECADE ( Drug – based ) REGIMEN RESPONSE ( % ) CR ( % ) OVERALL SURVIVAL ( m ) 1960 – 1970 (non-anthracycline) CMF, CMFP, CMFVP 50 – 60 5 – 10 15 – 18 1970 – 1990 (anthracycline) AC, FAC, FEC 50 – 80 5 – 20 17 – 25 1990 – 2000 (taxane) AT, ET, TAC 46 – 68 54 – 65 7 – 41 14 – 23
  • RESPONSES TO COMBINATION CHEMOTHERAPY AS FIRST LINE TREATMENT OF METASTATIC BREAST CANCER Partial or complete response 45 % to 80 % Complete response 5 % to 25 % Time to initial response (median) 4 to 8 wk Duration of response (median) 5 to 13 mos Survival of responders (median) 15 to 33 mos
  • ARE TAXANE - CONTAINING REGIMENS SUPERIOR TO NON TAXANE - CONTAINING ONES ?
  • MESSAGES FROM LARGE RANDOMIZED STUDIES IN METASTATIC BREAST CANCER
    • Combination chemotherapy is superior to single agent chemotherapy regarding response and survival
    • Anthracycline – containing regimens are superior to CMF-line regimens
    • Chemotherapy at standard doses is associated with longer survival than treatment at less than standard doses.
    • Taxanes -containing regimens show higher response rates and time to progression, but survival benefit is still controversial
  • H O R M O N O T H E R A P Y IN METASTATIC BREAST CANCER
  • RESPONSE OF HORMONAL THERAPIES IN METASTATIC BREAST CANCER Agent Response Rate (%) Range (%) Tamoxifen 32 16-52 Aromatase Inhibitors 32 16-43 LHRH Analogues 36 32-45 Progestins 30 9-67
  • TOXICITIES AND LONG – TERM EFFECTS OF ENDOCRINE THERAPY TAMOXIFEN Amenorrhea (>1/3), hot flashes, vaginal bleeding, thrombophlebitis, endometrial cancer. AROMATASE INHIBITORS Muscoloskeletal complaints. GnRH ANALOGUE Sexual dysfunction
  • GOLD STANDARDS IN ENDOCRINE THERAPY FOR ADVANCED BREAST CANCER
    • About 30% of unselected pts will respond to an endocrine therapy (med. duration 8-14 mos).
    • About 50-60% of pts rich in estrogen receptors will respond.
    • Pts responding to one endocrine therapy are likely to respond to subsequent hormonal manipulations.
    • For premenopausal pts: Ovarian function suppression plus Tamoxifen
    • For postmenopausal pts: Tamoxifen or aromatase inhibitors.
  • TARGETED TREATMENT IN METASTATIC BREAST CANCER
  • TRASTUZUMAB COMBINATIONS FOR METASTATIC BREAST CANCER Combination Response Rate % H + Doxorubicin /Cyclophosphamide 60 H + Epirubicin / Cyclophosphamide 64 H + Liposomal doxorubicin 58 H + Cisplatin 26 H + Viborelbine 60-84 H + Gemcitabine 32-62 H + Capecitabine 47 H + Taxol 41-81 H + Taxotere 55-76 H + Taxol/Carbo 68 H + Taxotere /Carbo 56 H + Taxotere / Cisplatin 79
    • Block the action of vascular endomethelial growth factor (VEGF)
    • For colorectal cancer,
      • renal cancer
      • breast cancer
      • NSCLC
    BEVACIZUMAB (Avastin)
  • BEVACIZUMAB (Avastin) EFFICACY IN METASTATIC BREAST CANCER Response Rate (%) PFS (wks) Overall Survival (mos) Bevacizumab + Capecitabine vs Capecitabine 19.8 % 9.1 % 4.86 4.17 15.1 14.5 p value 0.001 NS NS Bevacizumab + Paclitaxel vs Paclitaxel 48.0 % 23.4 % 11.4 5.8 26.5 24.8 p value < 0.0001 < 0.0001 NS
    • It is a tyrosine kinase inhibitor
    • Inhibits both EGFR / ErbB1 and HER-2 / ErbB2 tyrosine kinases
    • For breast cancer
    LAPATINIB (Tykerb)
  • LAPATINIB EFFICACY IN METASTATIC BREAST CANCER Response Rate (%) PFS (wks) Survival (mos) Lapatinib + Capecitabine vs Capecitabine 22.5 % 14 % 39.6 17.9 - p value NS p 0.001 NS Lapatinib + Paclitaxel vs Lapatinib 35 % 25.3 % No difference No difference p value p 0.008 Lapatinib + Trastuzumab vs Lapatinib 10.3 % 6.9 % 12.0 8.4 51.6 39.0 p value NS p 0.029 NS
  • PARP INHIBITORS [Polus (ADP-Ribose) polymerase inhibitors]
    • PARPs are also tested in other solid tumors i.e ovarian cancer, melanoma, etc.
    • PARPs inhibitors are novel agents capable of treating advanced triple-negative breast cancer and BRCA mutated breast cancers.
    • PARP inhibitors are a family of enzymes involved in multiple cellular processes, including DNA repair .
    • PARPs inhibitors are emerging as one of the most promising “ targeting ” drugs with the intended “target” being DNA repair.
  • Ongoing and Planned Trials with PARP - INHIBITORS
    • Phase I
      • Cisplatin + Olaparib
    • Randomized Phase II
      • Stage II/III Triple Negative Disease
      • Cisplatin alone vs Cisplatin plus Olaparib
    • Additional trials
      • Low dose cisplatin plus metronomic cyclophosphamide plus BSI-201
  • Efficacy of PARP Inhibitors in BRCA 1 / 2 mutated Breast Cancers : Synthetic Lethality Tutt A et al. The Lancet, Volume 376, Issue 9737, 2010, Pages 235-244 Olaparib 400 mg twice daily (n=27) Olaparib 100 mg twice daily (n=27) Objective response 11 ( 41% ; 25-59) 6 ( 22% ; 11-41) Complete response 1 (4%; 1-18) 0 Partial response 10 (37%; 22-56) 6 (22%; 11-41) Stable disease 12 (44%; 28-63) 12 (44%; 28-63) Progressive disease 4 (15%;6-32) 9 (33%;19-53)
  • PARP 1 Inhibitors Compound Route Phase Ongoing Trials Iniparib (BSI-201) Intravenous I-III Breast Veliparib Oral I-II Breast, ovarian Olaparib Oral I-II Breast, ovarian
  • BISPHOSPHONATES IN METASTATIC BREAST CANCER
  • BISPHOSPHONATES IN BREAST CANCER
    • MATERIAL : 19 RCTs
    • 1962 women with advanced breast cancer and bone metastases
    • RESULTS : i) Reduced the risk of developing a skeletal event by 14% (p< 0.00001)
    • ii) Significant improvements in pain (4 studies)
    • iii) Significant improvements in quality of life (2 studies)
    • iv) No effect on survival
  • MOST COMMON SIDE EFFECTS OF INTRAVENOUS BISPHOSPHONATES
    • Transient pyrexia 10 – 41%
    • Phlebitis at injection site 18%
    • Transient myalgia, arthralgia 10%
    • bone pain, malaise
    • Hypocalcemia 5 - 17%
  • TREATMENT LINES IN METASTATIC BREAST CANCER SURVIVAL GAIN 1 st LINE CX, HOR, TARG 3 rd LINE CX, HOR, TARG 2 nd LINE CX, HOR, TARG 12 – 16 months 12 – 16 months 6-9 months 12 – 16 months 6-9 months 4-6 months TOTAL (maximum) 16 mos 25 mos 31 mos CX = chemotherapy, HOR = Hormonal treatment, TARG = Targeted treatment
    • T HANK Y OU