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Affinitor in bc Affinitor in bc Presentation Transcript

  • "Targeted" Therapy for Advanced Breast Cancer "Affinitor" Aumkhae Sookprase!, MD ศูนย์มะเร็งอุดรธานี 22 พย 2556 Friday, November 22, 2013
  • (Locally advanced stage breast cancer) (Early stage breast cancer) (Metastatic stage) Friday, November 22, 2013
  • IN THE PAST • Prognosis in early stage depend on staging (how far cancer spread in your body) Friday, November 22, 2013
  • TODAY'S UNDERSTANDING • Prognosis in any stage depend on biology ! (nature or how aggressive cancer behave) Friday, November 22, 2013
  • TISSUE MICROARRAYS IN BREAST CANCER Friday, November 22, 2013
  • PROGNOSIS VARY BY MOLECULAR SUBTYPES Luminal A has best prognosis Basal & HER2 subtypes has worst prognosis Friday, November 22, 2013
  • THE "MUST" HAVE IHC IN EVERY BREAST CANCER HER 2 Ki-67 HER2 positive = 3+ E ER positive = at least 1% staining Friday, November 22, 2013
  • ER and PR and HER2 negative Triple negative (TN) Luminal A / B ER and/or PR positive and HER2 negative Friday, November 22, 2013 HER 2 HER 2 +, ER / PR -
  • ER and PR and HER2 negative Chemotherapy Triple negative tumor Friday, November 22, 2013
  • Anti-HER 2 HER2 positive tumor HER 2 +, ER / PR - Friday, November 22, 2013
  • HER 2 positive breast cancer Normal cell Friday, November 22, 2013
  • HER 2 positive breast cancer Normal cell Friday, November 22, 2013
  • Anti-hormonal ER positive tumor ER and/or PR positive and HER2 negative Friday, November 22, 2013
  • Growth of cancer cells Friday, November 22, 2013
  • (ER and PR and HER2 negative) Basal subtype Surgery Chemotherapy 4 - 6 cycles every 3 weeks Radiation ( size > 5 cms, lymph node involvement) Friday, November 22, 2013
  • (ER negative and HER2 negative) HER 2 subtype Surgery Anti- HER 2 (Trastuzumab ) 1 yr + Chemotherapy Radiation ( size > 5 cms, lymph node involvement) Friday, November 22, 2013
  • (ER positive and HER2 negative) Luminal subtype Surgery Anti-hormonal 5 yrs Radiation +/- ( size > 5 cms, lymph node involvement) Friday, November 22, 2013 Chemotherapy
  • Methods to inhibit ER in Early Stage TAMOXIFEN 1. NS-AIs : LET, ANA 2. Nucleus S-AI : EXE Post-menopausal Friday, November 22, 2013 Growth & proliferation
  • 2. Type of distant metastasis 1.Bone metastasis 2.Soft tissue metastasis (LN, subcutaneous) 3. Non life-threatening visceral Friday, November 22, 2013 1. Life-threatening visceral : pulmonary, liver 2. Multiple sites of metastasis
  • (survival) QoL Factors 1. Patient's factor : Performance status 2. Tumor's factor : Biology (tumor subtype) 3. Treatment's goal - Rapid response in patient with widespread metastasis - Toxicity profiles in each treatment Friday, November 22, 2013
  • Capecitabine Eribulin Taxanes Gemcitabine FAC Vinorelbine Chemotherapy Friday, November 22, 2013 Ixabepilone
  • Trastuzumab Anti-HER 2 Friday, November 22, 2013 Lapatinib
  • 58% ER positive tumors 1 HR+ 58% Anti-hormonal is a mainstay treatment 1Lertsanguansinchai Friday, November 22, 2013 P, et al. J Med Assoc Thai. 2002
  • Anti-hormonal Tamoxifen Fulvestrant Non-steroidal AIs : Letrozole, Anastrozole steroidal AI : Exemestane Megestrol acetate Estrogen Anti-hormonal Chemotherapy Friday, November 22, 2013 Anti-HER 2
  • Methods to inhibit ER TAMOXIFEN Pre-menopausal FULVESTRANT OFS (GnRH or surgical) 1. NS-AIs : LET, ANA 2. Nucleus S-AI : EXE Post-menopausal Friday, November 22, 2013 Growth & proliferation
  • (survival) QoL Factors 1. Patient's factor : Performance status 2. Tumor's factor : Biology (tumor subtype) 3. Treatment's goal - Rapid response in patient with widespread metastasis - Toxicity profiles in each treatment Friday, November 22, 2013
  • HR + MBC Life-treatening HR+ MBC Non - life-treatening HR+ MBC 1st line CT Response PD PD 2 nd line CT PD 3 rd line CT PD 4 th line CT PD Response 2 nd line PD Maintenance HT Response 3 rd line Maintenance HT PD Response Later line of CT Friday, November 22, 2013 1 st line Maintenance HT 4 th line Maintenance HT
  • HR + MBC Life-threatening HR+ MBC Non - life-threatening HR+ MBC PD with life - threatening metastasis 1st line CT Not response 1 st line HT Response 2 nd line HT 2 nd line CT 3 rd line HT 3 rd line CT 4 th line CT Later line of CT Friday, November 22, 2013 4 th line HT Later line HT
  • Early Stage Friday, November 22, 2013 Metastatic setting
  • Timeline of Approval for HR+ Advanced Breast Cancer: No New Regimens Approved in the Prior Decade Exemestane (1999) Tamoxifen (1977) Letrozole (1997) Fulvestrant (2002) Anastrozole (1995) 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Friday, November 22, 2013
  • Schema of treatment options for HR+, postmenopausal women following different adjuvant therapies Friday, November 22, 2013
  • Guideline for ER+/HER2- ABC • For post-menopausal women, the preferred 1st line ET is an AI; however, TAM remains a viable option in selected pts. Type and duration of adjuvant ET must be taken into account : 1A Cardozo F, Costa A, Norton L, et al. The Breast 2012. Friday, November 22, 2013
  • Must know definitions in aBC on ET • Primary (de novo) VS Secondary resistance 1. Primary (de novo) - Initial resistance (not response to therapy at all) 2. Secondary (acquired resistance) - Initial response then resistance Friday, November 22, 2013
  • Schema of treatment options for HR+, postmenopausal women following different adjuvant therapies Friday, November 22, 2013
  • Guideline for ER+/HER2- ABC • Optimal post-AI treatment is uncertain. Available options include, but are not limited to, TAM, another AI, fulvestrant and megestrol acetate : 1A Cardozo F, Costa A, Norton L, et al. The Breast 2012. Friday, November 22, 2013
  • Methods to inhibit ER TAMOXIFEN Pre-menopausal FULVESTRANT OFS (GnRH or surgical) 1. NS-AIs : LET, ANA 2. Nucleus S-AI : EXE Post-menopausal Friday, November 22, 2013 Growth & proliferation
  • Sequential benefit in ET treatment after 1 NS-AI "Partial non-cross resistant between AIs" Initial Second N ORR (%) CBR(%) A or L E 23 8.7 43.5 TTP (months) 5.1 E A or L 18 22.2 55.6 9.3 A E 12 - - 4.4 E A 11 - - 1.9 A E 50 8 44 5 A or L E 114 5 46 4 A or L E 31 19.4 54.8 3.2 A or L E 30 0 46.6 4 A or L E 60 20 38.3 3.2 A or L E 105 4.8 20 3.2 5 - 20 50 3-5 Mostly A or L Friday, November 22, 2013 E
  • Modest Benefit of Single-Agent Chemotherapy for Advanced BC Typical Clinical Outcomes Treatment Line Response Rate, % Median TTP, mo First-line 25 – 45 5–8 Second-line 15 – 30 2–5 Third-line 0 – 20 1–4 Subsequent lines Limited or no data Abbreviations: mo, months; TTP, time to progression. Burstein HJ. ASCO 2010. Metastatic Breast Cancer Oral Abstract Session. Friday, November 22, 2013
  • Mechanisms of Endocrine Resistant and Potential Molecular Target Friday, November 22, 2013
  • Friday, November 22, 2013
  • Friday, November 22, 2013
  • HR+ Advanced Breast Cancer E Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369. Friday, November 22, 2013
  • Mechanisms of AI resistance Friday, November 22, 2013
  • Mechanisms of AI resistance A. Ineffective inhibition of AIs Friday, November 22, 2013
  • Mechanisms of AI resistance B. Alternative sources of E Friday, November 22, 2013
  • Mechanisms of AI resistance D. Ligandindependent activation of Esignaling pathways Friday, November 22, 2013
  • HER2, FGFR, EGFR, IGF-1R HR+ Advanced Breast Cancer ER CoA ER P Src PI3K Ras AKT MAPK E S6KI mTOR ER P P P ER P CoA P P ERCoA P P CoA Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369. Friday, November 22, 2013
  • Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition •mTORC1 activates ER in a ligand-independent fashion1 •Estradiol suppresses the apoptosis induced by PI3K/ AKT/mTOR blockade2 •Hyperactivation of the PI3K/ AKT/mTOR pathway is observed in endocrineresistant breast cancer cells3 •mTOR is a rational target to enhance the efficacy of endocrine therapy Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28S36. Friday, November 22, 2013
  • Friday, November 22, 2013
  • Potential Therapeutic Target to Overcome Resistance of NS-AIs Friday, November 22, 2013
  • Friday, November 22, 2013
  • "Targeted" Therapy for Advanced Breast Cancer "Affinitor" Aumkhae Sookprase!, MD ศูนย์มะเร็งอุดรธานี 22 พย 2556 Friday, November 22, 2013
  • NEJM, Feb, 2012. Friday, November 22, 2013
  • Friday, November 22, 2013
  • Friday, November 22, 2013
  • Friday, November 22, 2013
  • DFS Friday, November 22, 2013
  • DFS Friday, November 22, 2013
  • Friday, November 22, 2013
  • Friday, November 22, 2013
  • Timeline of Approval for HR+ Advanced Breast Cancer: No New Regimens Approved in the Prior Decade Exemestane (1999) Tamoxifen (1977) Everolimus + exemestane (2012) Letrozole (1997) Fulvestrant (2002) Anastrozole (1995) 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Friday, November 22, 2013
  • BOLERO-2 : Most Common Adverse Events Friday, November 22, 2013
  • Clinically Notables AEs Associated with mTOR inhibition Stomatitis Non-infectious pneumonitis Infectious Hyperglycemia, hyperlipidemia Skin rash Friday, November 22, 2013
  • Time to Definitive Deterioration of QoL : clinical significant Friday, November 22, 2013
  • Stomatitis : Clinical manifestation ( all grade 59%, grade 3 : 8%) Aphthous like ulcers, discrete, well-demarcated with whitish pseudomembrane Typically develop acutely in the first cycle Severity peak within 2 weeks of treatment Friday, November 22, 2013
  • Rash : Clinical manifestation ( all grade 39%, grade 3 : 8%) Acne inform dermatitis Start with inflammatory lesion, papule, macule Distribute over and unusual areas : upper extremities, trunk, neck Friday, November 22, 2013
  • Non-infectious pneumonitis : Radiographic ( all grade 16%, grade 3 : 3%) Obtain base line CXR "diffuse ground glass or patchy infiltration" Friday, November 22, 2013
  • Management of Common Adverse Events: Noninfectious Pneumonitis Noninfectious pneumonitis may occur with everolimus and other mTORs1 • Asymptomatic (grade 1 = radiological lung changes only) • Symptomatic (grade 2 = not interfering with daily activities; grade 3 = interfering with daily activities; grade 4 = oxygen indicated) Diagnosis of noninfectious pneumonitis • Recommend consultation with pulmonologist • Follow dose-modification guidelines according to grade of pneumonitis • CT scan with lung windows and PFT as indicated; bronchoscopy with biopsy and/or bronchoalveolar lavage for grade 3 and 4 recommended 1. Atkins et al. J Clin Oncol. 2004;22:909-918. Friday, November 22, 2013
  • Everolimus Dose Level Modification Guidelines: Noninfectious Pneumonitis Worst Gradea Grade 1 Grade 2 Investigation Management CT scans with lung windows Repeat at least every 12 weeks No specific therapy until return to within normal limits CT scans with lung windows Repeat at least every 12 weeks until return to within normal limits Consider PFTb Consider bronchoscopy with biopsy and/or BAL Symptomatic only Corticosteroids if symptoms are troublesome Everolimus Dose 100% Reduce everolimus 1 dose level until recovery to ≤ grade 1 Everolimus may also be interrupted if symptoms are troublesome If not ≤ grade 1 within 3 weeks withdraw patients from study Everolimus dose cannot be escalated Grade 3 As for grade 2 with PFT Repeat at least every 6 weeks until return to within normal limits Corticosteroids if of Bronchoscopy with biopsy and/or noninfectious origin BAL recommended Taper as indicated Exclude infection/progression of underlying malignancy Hold everolimus until recovery to ≤ grade 1 If of clinical benefit, may restart everolimus within 3 weeks at next lowest dose level Grade 4 As for grade 3 Discontinue everolimus Friday, November 22, 2013 As for grade 3
  • BOLERO-2 : Most Common Adverse Events Friday, November 22, 2013
  • Reverse or delay resistance mTOR inhibitor Anti-hormonal Tamoxifen Fulvestrant Non-steroidal AIs : Letrozole, Anastrozole steroidal AI : Exemestane Megestrol acetate Estrogen Anti-hormonal Chemotherapy Friday, November 22, 2013 Anti-HER 2
  • Friday, November 22, 2013