Challenging cases in breast cancer

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					Challenging Cases in Cancer:
  Advanced Breast Cancer


           Linda T. Vahdat, MD
   Medical Director, Breast Cancer Program
     Weill Medical College of Cornell University
       New York Presbyterian Hospital
                New York, NY
               Goals of Program

• Review approach to goals of therapy in advanced
  breast cancer
• Integrate existing clinical data in the day-to-day
  management of advanced breast cancer
Management of Advanced Breast Cancer:
        Efficacy vs. Toxicity
    Options for Advanced Breast Cancer


          Chemotherapy                                      Hormonal
        Oral meds- capecitabine,
                                                             Therapy
        Vincas, taxanes, camptothecins,                Tamoxifen, SAIs,
        liposomal preparations,                        fulvestrant (2ME)
        nanoparticle preparations
        (ixabepilone, eribulin)
                                           Biologics
                                  Trastuzumab, bevacizumab,
                                  Lapatinib (sunitinib, tipifarnib)




Non-FDA approved drugs in parentheses
          Advanced Breast Cancer

• No standard approach
• Many options
• QOL important endpoint
• Site specific palliation (i.e. VAT, bisphosphonates)
• Many clinical trials available
• Improvement in survival
   – Median 4.3 years
Chemotherapy for Stage IV Breast Cancer

  • Options:
     – Taxanes- vary the schedule to re-induce response, use of
       different delivery systems
     – Capecitabine +
     – Vinorelbine +
     – Anthracyclines + liposomal preparations, epirubicin
     – Gemcitabine +
     – Irinotecan
Stage IV Breast Cancer Chemotherapy

• Modest differences in response rates
• No real effect on overall survival
• Toxicity issues important when palliation the goal
Common Regimens for Stage IV Breast Cancer

  Agent                    CR (%)               PR (%)              ORR (%)             TTP (mos)

  Paclitaxel                    5                   20                   25                   4.6

  Docetaxel                     2                   30                   32                   7.5

  Nab-paclitaxel               NR                  NR                    34                   5.2

  Capecitabine                  2                   18                   20                   8.1

  Vinorelbine                   5                   20                   25                   3.0

  Gemcitabine                   6                    6                   12                   3.0


     Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005
   Common Regimens Used in MBC:
    Grade 3/4 Hematologic Toxicity
                            100

                            90

                            80

                            70

                            60
               % patients




                                                                        Neutropenia
                            50                                          Febrile neutropenia
                                                                        Platelets
                            40

                            30

                            20        15

                            10
                                  2        2    0       0       1
                             0
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Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005
Common Regimens Used in MBC:
Grade 3/4 Non-hematologic Toxicity
                30


                25


                20
                                                                            paclitaxel
                15                                                          docetaxel
                                                                            nab-paclitaxel
                10                                                          capecitabine
                                                                            gemcitabine
                 5
                                                                            navelbine

                 0




Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005
                   Case Studies

• Real patients
• No wrong answer
• Integrate goals of patients and physician into final
  decision
                     Case #1: DG

• 72-year-old woman with a h/o bilateral breast cancer
   – 1978 RMRM: T = 2.cm, N = 0/24, ER/PR+
      • No further therapy
   – 1990 LMRM: T = 1.0 cm, N = 0/12, ER/PR+
      • Tamoxifen x 5 years
   – 1998 CW nodule excised: c/w ILC, ER/PR+, HER2-
   – EOD: sub-centimeter pulmonary nodules
   – Anastrazole started with resolution of pulmonary nodules
                    Case #1: DG

• 2006: routine follow-up physical exam:
   – Noted to have large pre-sternal mass
   – Asymptomatic
   – CT chest abd pelvis: 8 cm mass adjacent to sternum
     abutting but not invading pericardium
                Case #1: DG

What treatment would you recommend?
 Hormonal therapy
 Chemotherapy
 Radiation therapy
 Hospice
                  Case #1: DG

What treatment would you recommend?
 Hormonal therapy
 Chemotherapy
 Radiation therapy
 Hospice

Recommended Approach:
• All options are appropriate but would favor hormonal
  therapy
Reasons to Consider Hormonal Therapy
           for This Patient
 • Elderly
 • Asymptomatic from current cancer
 • Long natural history of breast cancer
 • 9-years of benefit from an aromatase inhibitor
 • RT will only manage CW mass and large area to
   irradiate
                 Hormonal Options

• Another aromatase inhibitor
   – Exemestane
   – Letrozole
• Estrogen receptor down-regulator
   – Fulvestrant
                        Clinical Data
• Use of fulvestrant after an aromatase inhibitor:
   – Fulvestrant in women with advanced breast cancer after
     progression of prior aromatase inhibitor: NCCTG Trial 0032.
     Ingle JN et al. JCO 2006

• Use of an aromatase inhibitor after failure of an
  aromatase inhibitor:
   – Activity of exemestane in metastatic breast cancer after
     failure of nonsteroidal aromatase inhibitors. Lonning et al. JCO
     2000
   – Sequential use of aromatase inactivators and inhibitors in
     advanced breast cancer. Bertelli et al. Proc Amer Soc Clin Oncol
     2002
Fulvestrant in Women with Advanced Breast Cancer
   After Progression of Prior Aromatase Inhibitor:
                   NCCTG 0032

  Eligibility criteria
  • ER and/or PR+ breast cancer
  • Measurable disease
  • Progressive disease after a 3rd generation AI in addition to
    another hormonal agent
  • One prior chemo regimen for MBC
  Treatment: Fulvestrant 250 mg IM Q 28 days
  Evaluation on study: Month 1 and then Q 3 months




                                                         Ingle JN et al. JCO 2006
                   NCCTG 0032
• Entered: 80 patients
• Evaluable: 77 patients
• Disease sites:
   – 88% visceral predominant disease
   – 73% 2 prior hormone therapies
   – 32% prior chemotherapy




                                        Ingle JN et al. JCO 2006
           NCCTG 0032: Results

• Partial responses: 11/77= 14.3%
• Stable disease ≥ 6 months16/77 = 20.8%
• Clinical benefit rate: 35%
• Median TTP = 3 months
• Median duration of response 11.4 months
• Clinical benefit rate 54% in those who had not
  received prior tamoxifen



                                             Ingle JN et al. JCO 2006
 Clinical Benefit of Fulvestrant in Post Menopausal Women with
     Primary or Acquired Resistance to Aromatase Inhibitors:
Final Results of Phase II Swiss Group for Clinical Research Trial
                           (SAKK 21/00)

    • Two groups of patients:
       – Group A (N = 70)AI responsive disease
       – Group B (N = 20) AI resistant disease
    • Treatment: fulvestrant 250 mg IM Q 28 days




                                                 Perey et al. Annals of Oncology 2007
             SAKK 21/00: Results
• Patient characteristics:
   – AI pretreatment: 100%
   – Tam/toremifene pretreatment: 84%
   – Bone mets: 64%
   – Liver mets: 45%
• Clinical Benefit rate (CR,PR, SD ≥ 6 months): 30%
• No difference by prior AI response




                                        Perey et al. Annals of Oncology 2007
Activity of Exemestane in Metastatic Breast Cancer After
       Failure of Nonsteroidal Aromatase Inhibitors

    • Phase II trial: N = 242 pt
    • Exemestane: 25 mg QD after failure of AI
    • Response rate: 16/242 6.6%
    • Stable disease rate ≥ 6 months: 42/242 (17%)
    • Clinical benefit rate: 24.3%
    • Median duration of response: 54 weeks
    • Median duration of treatment: 10 weeks



                                               Lonning PE et al, JCO 2000
Summary of Fulvestrant or Aromatase Inhibitor
           After Failure of an AI

                                         RR          SD ≥ 6 mos               CBR          Med. TTF
    Treatment               N
                                         (%)            (%)                   (%)           (mos.)
Fulvestrant after AI

   NCCTG 0032              80            14.3              20.8                 35             11.4

   SAKK 21/00              90                                                   30

Exemestane after AI

     Lonning              242             6.6                17               24.3             12.2

                 AI= aromatase inhibitor, RR= response rate, SD= stable disease, CBR= clinical benefit rate
                 ( CR,PR and SD≥6 mos); TTF= Time to treatment failure (ie. median duration of response)
              Case #1: Outcome

• Patient in an ongoing response to fulvestrant for 1
  year at present
                    Case #2: DCR

• 45-year-old AA woman vocalist with stage 2 breast
  cancer
   – 1999: LMRM
   – T = 3.2 cm, N = 0/10, ER/PR/HER2-
   – AC q 3 w x 4
• 2006: difficulty hitting the high notes and DOE during
  dance routines
                Case #2: DCR

• 2006: biopsy of CW mass: c/w BC (ER/PR/HER2-)
• EOD: multiple pulmonary nodules and extensive hilar
  and subcarinal adenopathy compressing bronchi
               Case #2: DCR

What treatment would you recommend:
 Chemotherapy alone
 Chemotherapy + biologic
 Hospice
                Case #2: DCR

What treatment would you recommend:
 Chemotherapy alone
 Chemotherapy + biologic
 Hospice


Recommend Approach
• Would favor a regimen that would give the highest
  response in the quickest amount of time because she
  is symptomatic
                  Case #2: DCR

• Chemotherapy: single agent or combination
• Chemotherapy + biologic
   – Paclitaxel + bevacizumab
   – Capecitabine + bevacizumab
               Treatment Issues


• Single agent vs. combination?
• Rapid response rate?
• Any special considerations for triple negatives?
      Single Agent vs. Combination

• Response rates higher with combination therapy
• Time to progression better
• Overall survival similar
• Toxicity increased with combination
               Trials of Combination vs. Monotherapy
                     in Advanced Breast Cancer
                                                                  RR         TTP           OS
             Author                                     N
                                                                  (%)       (mos.)        (mos.)
             Sledge (E1193)
               Doxorubicin                             224        36          5.6            19
               Paclitaxel                              229        34          5.8            22
               Combination                             230        47            8            22
             Bonneterre
               Docetaxel                               86         43          6.5            NA
               5FU/Vinorelbine                         90         34          5.1            NA
             O’Shaughnessy
               Docetaxel                               256        30          4.2           11.5
               Docetaxel + Capecitabine                255        42          6.1           14.5
             Albain
               Paclitaxel                              262        26          2.9           15.8
               Paclitaxel + gemcitabine                267        32          5.2           18.5
Significant differences in bold, RR = response rate; TTP = time to progression; OS = overall survival.
        Sledge, JCO 2003; Bonneterre, Br J Ca 2002; O’Shaughnessy, JCO 2002; Albain, Proc Amer Soc Clin Oncology 2004
             Capecitabine Data

• Oral 5FU prodrug*
• Response Rate first-line1,2: 30-58%
• Response Rate for anthracycline and taxane
  pretreated3,4: 14 to 29%
• Median time to response: 12 weeks



                                                            1O’Shaughnessy, Ann   Oncol 2001
                                            2Reynoso, Breast Ca Res Treat 2005 Suppl(S219)
                                                                           3 Blum, JCO 1998

                                                      4Vahdat, Proc Amer Soc Clin Oncol 2007

        *Good review: Seidman A, The Oncologist 2002;7(suppl 6):20-28 www.TheOncologist.com
                Docetaxel Data

• Antimicrotubule agent*
• Response Rate first-line1,2: 32 to 54%
• Median time to response: 12 weeks




                                      1Hudis   C, J Clin Onc 1996; 2 Jones S J Clin Oncol 2005
                     *Good review: Nabholtz JM, Semin Oncol. 2002 Jun;29(3 Suppl 12):28-34
              Bevacizumab Data

• Humanized monoclonal antibody to VEGF-A*
• Improves survival when added to chemotherapy in
  colon and NSCLC
• Single-agent activity in breast cancer1




                                 1Cobleigh,   M Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24
                    *Good review: Traina, T et al Hematol Oncol Clin N Am (21)2007, 303-319
Chemotherapy and Bevacizumab for MBC

  • Capecitabine: first and second-line therapy1,2
  • Metronomic cyclophosphamide + mtx3
  • Paclitaxel: first-line therapy4




                                       1Sledge     Proc Amer Soc Clin Oncol 2007
                                                                2Miller   JCO 2005
                                      3Burstein   Breast Ca Res Treat 2005 Suppl
                                         4Miller   Proc Amer Soc Clin Oncol 2005
                        ECOG 2100
             R
             A                            Paclitaxel
             N
                                           N = 350
             D
First-line
  MBC
             O
             M
             I                  Paclitaxel + Bevacizumab
             Z                              N = 365
             E
             D
                 Paclitaxel dose: 90 mg/m2 on day 1,8,15 Q 28 days
                     Bevacizumab dose: 10 mg/kg on Day 1, 15


                                                         Miller, K et al. ASCO 2005
               ECOG 2100

                            Paclitaxel +
Treatment     Paclitaxel                     P-value
                           Bevacizumab

Response
                14.2           28.2        P < 0.0001
 rate (%)
Median time
     to                                    P < 0.0001
                 6.1            11
progression                                HR = 0.51
 (months)

  Overall
                 ns             ns         HR = 0.84
  survival


                                           Miller, K et al. ASCO 2005
Phase III Trial Capecitabine ± Bevacizumab

                                    Capecitabine +
    Treatment        Capecitabine                           P-value
                                    Bevacizumab

  Response rate
                         9.1            19.8              P = 0.001
      (%)

  Median time to
   progression           4.17           4.86               HR = 0.98
    (months)

  Overall survival       15.1           14.5                    NS


                                                     Miller, K et al. ASCO 2005
Metronomic Cyclophosphamide + Methotrexate
          (CM) ± Bevacizumab(b):
        Randomized Phase II Study

                                                                TTP
           Treatment           No. pts      RR(%)
                                                               (mos)

               CM                 21            10               2.2

              CMB                 34            29               5.5


      RR = response rate; TTP = time to progression




                                           Burstein et al, Breast Cancer Res Treat Suppl 2005
   Any Role in Special Populations?

• Preliminary data from E2100 suggests a PFS benefit
  in triple negative population
   – ER/PR +, HR = 0.30 (CI 0.29 - 0.53)
   – ER+/PR -, HR = 0.86 (CI 0.52 - 1.43)
   – ER/PR -, HR = 0.47 (CI 0.35 - .63)
             Case #2: Outcome

• Had more than a partial response in lungs and a CR
  in chest wall
• Opted to come off treatment because of fatigue and
  neuropathy a year ago and has stable disease and no
  therapy since that time
                  Case #3: RS

• 52-year-old woman diagnosed with an IBC in 1/2003
• Neoadjuvant chemotherapy with AC followed by
  paclitaxel q 2 w (clinical partial response)
• LMRM, T = 6 cm, N = 12, ER/PR+, HER2- by FISH
• 11/2003: lung, liver, bone, and regional nodal
  metastases, ER/PR+ and HER2-
• Pain from bone mets
                   Case #3: RS

What treatment would you recommend:
 Hormonal therapy
 Chemotherapy
 Clinical trial
 Hospice
                     Case #3: RS
What treatment would you recommend:
 Hormonal therapy
 Chemotherapy
 Clinical trial
 Hospice

Issues to Considers
• Heavily pre-treated, symptomatic, large disease burden and
    short disease free interval

Treatment Recommendation
•   Clinical trial
Epothilones: Ixabepilone (BMS-247550)
• New antineoplastic class - the natural epothilones and their analogs




     S. cellulosum               Epothilone B         Ixabepilone

• Low susceptibility to tumor resistance mechanisms
   – MRP-1 and P-gp efflux pumps
   – b (III) tubulin overexpression
   – b tubulin mutations
• Activity in multiple tumor models
• Demonstrated pre-clinical synergy with capecitabine
   Ixabepilone Phase II Data in Breast Cancer
                45         42




                30
      ORR (%)




                                              22
                                                                                     19             18 pCR

                15                                               12




                0
                        Roché1               Low2         Conte3                 Thomas4            Baselga5
                          After            Taxane-    Taxane-resistant         Multiresistant      Neoadjuvant
                        adjuvant       pretreated MBC      MBC                 (anthra / tax /     T2-4, N0-3,
                         anthra                                                 cape) MBC              M0

 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol
2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660.
                                                      5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.
Study Design: International, Randomized,
       Open-label, Phase III Trial
                                                       Ixabepilone
                                              (40 mg/m2 IV over 3 hr d1 q3wk)
                                                          +
                                                      Capecitabine
    Metastatic or locally                   (2000 mg/m2/day PO 2 divided doses
  advanced breast cancer                              d1-d14 q3wk)
                                                         N = 375
        RESISTANT
     to anthracyclines
        and taxanes                                   Capecitabine
          N=752                             (2500 mg/m2/day PO 2 divided doses
                                                      d1-d14 q3wk)
                                                         N = 377



 Stratification
 • Visceral metastases          • Anthracycline resistance
 • Prior chemotherapy for MBC   • Study site
                      Response Rate
                              Investigator                      IRR
                      Ixabepilone                    Ixabepilone
                           +         Capecitabine                Capecitabine
                                                          +
                      Capecitabine                  Capecitabine
% Response                             N = 377                     N = 377
                        N = 375                        N = 375
ORR (CR + PR)              42                23         35                14
                                P < 0.0001                   P < 0.0001
Stable disease             36                38        41             46

Progressive disease        14                29        15             27

Unable to determine         8                10        9              12
                                         Progression-free Survival
                                    by Independent Radiologic Review
                              1.0
                                                                              Median        95% CI
Proportion Progression Free




                                            Ixabepilone + Capecitabine        5.8 mos      (5.5–7.0)
                              0.8
                                            Capecitabine                      4.2 mos      (3.8–4.5)


                              0.6
                                                                         HR: 0.75 (0.64–0.88)

                                                                              P = 0.0003
                              0.4


                              0.2


                               0
                                    0   4   8       12        16         20      24        28        32   36

                                                                Months
Grade 3/4 Non-hematologic Toxicities

                 80                                              Ixabepilone + Capecitabine (N = 369)

                                                                 Capecitabine (N = 368)
                 60
 % of Patients




                 40

                      23
                               18 17
                 20
                                       9       8             9
                                                         6         4
                                           3                           2      3   2       3   2    3
                           0                       0.3                                                  0
                 0
              Case #3: Outcome

• Enrolled in BMS 046 and randomized to ixabepilone
  and capecitabine arm
• Had a partial response that was clinically significant
  and was on study for 13 months. Taken off for
  progression
                  Case #4: IHA

• 55-year-old woman with newly diagnosed Stage IV
  breast cancer with massive adenopathy in right axilla
  rending limited motion in her arm
• No neurologic symptoms and she ignored problem
  until she was unable to go to work as a operator
• Biopsy c/w metastatic breast cancer, ER+/PR -,
  HER2- by FISH
• Rest of evaluation unremarkable except for bone
  metastases
                 Case #4: IHA

What treatment would you recommend:
 Hormonal therapy
 Radiation therapy
 Chemotherapy
 Hospice
                 Case #4: IHA

What treatment would you recommend:
 Hormonal therapy
 Radiation therapy
 Chemotherapy
 Hospice


Treatment Recommendation
• Chemotherapy
            Treatment Issues: IHA

• Many chemotherapy options.
   – Want to accomplish rapid disease control without significant
     toxicity.
• Goal would be to cytoreduce to no symptoms and
  then place on hormonal therapy
          Chemotherapy Options

• Anthracyclines
• Taxanes: paclitaxel, docetaxel, nab-paclitaxel
• Capecitabine
• Gemcitabine
• Vinorelbine
  First-line Chemotherapy For MBC

Agent                              N                    RR (%)                 TTP (mos)

Capecitabine1                     61                        30                      4.1

Gemcitabine2                      35                        37                      5.1

Vinorelbine3                     157                        41                        6

Paclitaxel4                      224                        25                      3.6

Docetaxel4                       225                        32                      5.7


RR = response rate; TTP = time to progression

        1O’Shaughnessy, Ann   Oncol 2001; 2Blackstein, Oncology 2002; 3 Fumoleau, JCO 1993; 4Jones, JCO 2005
                   Nab-paclitaxel

• Albumin-bound paclitaxel
• Advantages: no premeds
   – Cremophor free
   – Shorter infusion time
• Might make use of gp 160-albumin mediated receptor
  transport across endothelial cells
                               Nab-paclitaxel

                                                                                               Med TTP
Trial                 N           Setting             Schedule               RR (%)
                                                                                                (wks)

Ibrahim1              63          No limit        300 mg/m2 Q3w                  48                 27


                                                   125 mg/m2 QW
Mirtschung2           23          1st line                                       57                 NR
                                                   (3 out of 4 wks)

Gradishar3                                         260 mg/m2 vs.
nab-paclitaxel       460          1st line         175 mg/m2 Q               33 vs. 19         23 vs. 17
vs. paclitaxel                                          3W
Significant differences in Bold; RR = response rate, TTP = time to
progression; NR = not reported

                       1 Ibrahim, JCO 2005; 2 Mirtschung, Breast Ca Res Treat Suppl 2006; 3 Gradishar, JCO 2005
              Case #4: Outcome

• Patient had a near complete response to nab-
  paclitaxel and eventually came off of therapy due to
  toxicity (neuropathy)
   – This was chosen because she wanted to minimize her time
     in the office (Q 3 w schedule)
• Doing well on letrozole
Treatment of Advanced Breast Cancer
            Conclusions
• Many varied approached to managing advanced
  breast cancer
• Input from patient important in selecting a treatment
• Many new drugs being developed

				
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