Understanding Breast Cancer Guidelines

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  • 1. Understanding Breast Cancer Guidelines Rowan Chlebowski, MD, PhD
  • 2. International Treatment Guidelines
    • Provide the clinician with recommendations developed from the consensus opinions of international experts based on their interpretation of the most recent clinical data
    • Since 1978, St. Gallen conferences have developed consensus opinions for managing early breast cancer
      • Recognised as the leading European treatment guidelines
    • In the US, St. Gallen guidelines are strongly supported by both the American Society of Clinical Oncology (ASCO) and t h e National Comprehensive Cancer Network (NCCN) guidelines
  • 3. St. Gallen Breast Cancer Guidelines
    • Guideline recommendations for adjuvant systemic therapy
      • Advantages
        • Panel consists of international experts in the field of breast cancer
        • Guidelines are based on current clinical evidence
        • Panelists address clinical scenarios in a half-day public forum with a discussion-type format
        • Consensus is generated at the panel session by audience vote
        • Recommendations are published in a peer-reviewed journal
      • Limitations
        • Definition of risk is general and based on few criteria
        • Many recommendations are not specific and open to interpretation
        • Regional differences in rating relevance of study data
        • Guidelines are informative rather than prescriptive
    Goldhirsch et al. Ann Oncol . 2005;16:1569.
  • 4. ASCO and NCCN Breast Cancer Guidelines
    • ASCO recommendations and NCCN treatment guidelines are generated by expert consensus using a more rigorous process than the St. Gallen guidelines
    • ASCO guidelines are based on evidence from relevant publications, conference presentations, and additional data requested from pharmaceutical companies; greater weight is given to published randomised trials 1
    • All NCCN guideline recommendations are weighted by level of clinical evidence and degree of panel consensus reached through a continuous review and feedback process 2
    • ASCO and NCCN guidelines are highly detailed and prescriptive
    • Winer et al. J Clin Oncol. 2005;23:619.
    • NCCN. http://www.nccn.org/professionals/physician_gls/about.asp.
  • 5. St. Gallen Breast Cancer Guidelines 2007 Update
  • 6. St. Gallen – Endocrine Responsiveness “Practical” Clinical Subgroups ER and PR absent ER and PR low/int and/or any of these Both receptors high levels
    • PgR absent
    • UPA/PAI-1 high
    • HER-2 overexpressed
    • Increased proliferation
    • High grade
    No No No No No Chemo only options Chemo adds to hormonal Chemo doesn’t work Absent Endocrine- responsiveness Uncertain Sure
  • 7. Preferred and Alternative Treatment Regimens Tam = tamoxifen; AI = aromatase inhibitor; OFS= ovarian function suppression; GnRH=gonadotropin-releasing hormone; N = node; CT=chemotherapy Goldhirsh et al. Ann Oncol. 2007;18:1133. Combinations of cyclophosphamide, 5-fluorouracil, and an anthracycline Sequence of anthracycline and cyclophosphamide followed by paclitaxel or docetaxel Cannot be viewed as a standard treatment in women with a primary tumor <1 cm and no axillary node involvement Commencement with or after CT equally acceptable GnRH only (if pregnancy planned) AI + OFS (if Tam contraindicated) Tam (5 y) ± OFS with GnRH Premenopausal Chemotherapy Trastuzumab Tam (5 y) -> AI (not prospective; in presence of N+ disease) Initial AI (HER2+ or high risk) Accepted alternative Tam (5 y) Tam (2-3 y) -> AI Endocrine Therapy Preferred Postmenopausal
  • 8. St. Gallen 2007 Breast Cancer Guidelines: Endocrine Therapy for PMW
    • Supports initial adjuvant AI use in those taking SSRI antidepression medication (due to potential TAM interactions), high-risk patients, or those with HER2+ disease
    • Prefers switch from TAM to an AI after 2-3 y vs TAM for 5 y
    • Strongly endorses extended adjuvant AI therapy for patients at increased risk of recurrence (ie, node-positive)
    • Total optimal duration of adjuvant endocrine therapy is 5-10 y
    PMW = postmenopausal women; SSRI = selective serotonin reuptake inhibitor. Goldhirsh et al. Ann Oncol. 2007;18:1133.
  • 9. NCCN Clinical Practice Guidelines for Breast Cancer 2008 Update
  • 10. 2008 NCCN Breast Cancer Treatment Guidelines: Adjuvant Endocrine Therapy pT1, pT2, or pT3 and pN0 or pN1mi (≤2 mm axillary node metastasis) Node positive (≥1 metastases >2 mm to ≥1 ipsilateral axillary lymph nodes) Tumor ≤ 0.5 cm or Microinvasive or Tumor 0.6-1.0 cm, well differentiated, no unfavorable features Tumor 0.6-1.0 cm, moderate/poorly differentiated or unfavorable features Tumor >1 cm pN0 pN1mi Adjuvant endocrine therapy ± adjuvant chemotherapy Adjuvant endocrine therapy Consider adjuvant endocrine therapy No adjuvant therapy Adapted with permission from 2008 NCCN guidelines. Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab if HER2+ Consider 21-gene RT-PCR assay Low score (<18) Intermediate Score (18-30) Not done High score (≥31) HR positive disease
  • 11. NCCN Breast Cancer Guidelines Adjuvant Endocrine Therapy Postmenopausal AI for 5 y (category 1) Tamoxifen for 2-3 y Tamoxifen to 4.5-6 y AI to complete 5 y (category 1) or longer (category 2B) AI for 5 y (category 1) Women with contra-indication to AIs, who decline AIs or who are intolerant of the As, tamoxifen for 5 y (category 1) AI: Aromatase Inhibitor National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology – Breast Cancer. V.2.2008. At: www.nccn.org.
  • 12. ASCO Technology Assessment Recommendations 2004 Update
  • 13. ASCO Guidelines for Use of Adjuvant AIs in PMW With HR+ Breast Cancer
    • An AI (ANA or LET) may substitute for TAM as initial adjuvant therapy to reduce the risk of recurrence
    • Those currently on TAM may consider switching to an AI after 2-5 years of TAM therapy
    • Women who switch to an AI may continue this therapy for 2-3 more years, but no longer than 5 years
      • Treatment with an AI for >5 y has not been studied and should only be done in the context of a clinical trial
    HR+ = hormone receptor – positive; ANA = anastrozole; LET = letrozole. Winer et al. J Clin Oncol. 2005;23:619.
  • 14. ASCO Guidelines for Use of Adjuvant AIs in PMW With HR+ Breast Cancer (cont’d)
    • There are no data to recommend taking TAM after an AI
    • In addition, women who develop invasive HR+ breast cancer while taking TAM for prevention, and women who cannot take TAM because of high risk of severe side effects or who had to stop TAM because of severe side effects, might be advised to consider using an AI
    • It is not known whether the AIs can be used interchangeably
      • Therefore, using the agent with the most data relevant to each individual clinical setting is favoured
    Winer et al. J Clin Oncol. 2005;23:619.
  • 15. Regional Guidelines
  • 16. NICE Assessment on Hormonal Therapies for Early Breast Cancer: Key Conclusions
    • Relative to TAM, AIs improve clinical outcomes when used within their licensed indications as primary adjuvant treatment, in unplanned switching, or as extended adjuvant treatment
    • AIs are cost-effective when individually compared with T A M
    • In extended adjuvant treatment, letrozole is cost-effective compared with placebo/no treatment
    NICE = National Institute for Health and Clinical Excellence (UK).
  • 17. AGO Recommendations 2007: Adjuvant Endocrine Therapy for PMW *Up to 30 months. AGO Guidelines. http://www.ago-online.de/download/00GuidelinesEnglish.pdf. + B 2b EXE for 5 y + B 2b ANA for 3 y + D 4 LET for 5 y – long TAM-free interval* ++ B 1b LET for 5 y – N+ disease + B 1b LET for 5 y – overall AI after 5 y of TAM Extended Adjuvant + B 1b ANA or LET for 5 y ++ B 1b EXE or ANA after 2-3 y of TAM ++ A 1a TAM for 5 y (vs 2 or 1 y) AGO Grade of Recommendation Oxford Level of Evidence Adjuvant
  • 18. AGO Recommendations 2008: Adjuvant Endocrine Therapy for PMW *Up to 30 months. LOE = level of evidence; GR = grade of recommendation. AGO Guidelines available at: http://www.ago-online.com/download/00GuidelinesEnglish.pdf (Guidelines Breast 2008 Version 1.1). Extended Adjuvant + D 4 LET for 5 y – long TAM-free interval* + B 2b ANA for 3 y + B 2b EXE for 5 y + A 1b LET for 5 y – overall ++ B 1b LET for 5 y – N+ disease AI after 5 y of TAM ++ B 1b ANA or LET for 5 y ++ B 1b EXE or ANA after 2-3 y of TAM ++ A 1a TAM for 5 y (vs 2 or 1 y) AGO Grade of Recommendation Oxford Level of Evidence Adjuvant
  • 19. Breast Cancer Guidelines: Conclusions
    • The most recent international (St. Gallen) and US (ASCO, NCCN) guidelines were reviewed for adjuvant AI therapy recommendations in PMW with HR+ breast cancer
    • St. Gallen
      • Risk of recurrence and treatment options were most strongly tied to endocrine responsiveness
      • Preference for sequencing TAM to AI; use of AI after 5 y of TAM only in node-positive patients
    • NCCN
      • Recommends AI for 5 y, AI to complete 5 y after 2-3 y of TAM, and AI for 5 y after 4.5-6 y of TAM
    • ASCO
      • Recommends AI for 5 y and AI after 2-5 y of TAM for no longer than 5 y on the AI