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Sant Gallent y ESMO 2019

Eva María Ciruelos Gil. Madrid

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Sant Gallent y ESMO 2019

  1. 1. Actualización 2019: San Gallen, ESMO, SABCS Dr Eva M Ciruelos Servicio Oncología Médica, Unidad Cáncer de Mama Hospital Universitario 12 Octubre HM CIOCC
  2. 2. Aspectos significativos de St Gallen 2019
  3. 3. Treatment guidelines are no longer driven exclusively by the anatomic stage of the tumor or the histological subset of breast cancer. Decisions about optimal surgical, radiation therapy and medical approaches are increasingly tailored based on the initial response to neoadjuvant systemic treatment (NST). These developments demand that routine care be provided by an experienced multidisciplinary team.
  4. 4. Sophisticated pathology and genomic signatures assays substantially refine the anticipated prognosis for long-term outcomes and thus inform treatment recommendations. - For some patients there is a clear move to escalate therapy, such as longer durations of antiestrogen treatment, more utilization of ovarian function suppression (OFS), treatment for residual tumor after neoadjuvant systemic therapy, and dual targeting with anti- HER2 drugs. - In other settings, there is a movement to de-escalate treatment, including the shortening or omission of adjuvant chemotherapy, the avoidance of axillary surgery, and shortened courses of radiation treatment.
  5. 5. Tratamiento quirúrgico: márgenes y V Axilar Nipple and skin sparing mastectomy. Caution ir close proximity of the tumor to the skin Controversy fon preservation of nipple areolar complex if central tumors
  6. 6. Tratamiento quirúrgico: márgenes y V Axilar - In case of focally positive margins: re-excision (if extent not minimal) - If area of focally involved margin < 1mm, outweight risk and burden of re- excision - Recents studies in population based registries: limited focal positive margins with RT with a boost to the primary tumor bed associated with low risk of tumor recurrence (2,9 vs 1,1 % at 5 years)
  7. 7. Tratamiento quirúrgico: G Centinela y V Axilar - Sentinel node biopsy (SNB) as standard approach in cN0 and breast conserving sx - Elderly pts with clinical stage I and favorable biology: may not need SNB (IBCSG 10-93) - ACOSOG Z11 trial, a study of women with cT1-2, cN0 cancers tumor involvement of 1 or 2 sentinel lymph nodes completion axillary dissection is not indicated when patients will be receiving post-lumpectomy radiation therapy and appropriate systemic adjuvant therapy - If tumor size > 5cm and 1-2 positive nodes. Consider omitting axillary dissection if axilla included in Rt - If MT and 1-2 positive nodes: Axillary dissection or regional RT therapy (AMAROS trial)
  8. 8. Tratamiento neoadyuvante: indicaciones - ventajas Implications in the defining the optimal extent of surgical and RT regimens
  9. 9. Tratamiento quirúrgico: márgenes y V Axilar After NST, optimal resection is removal of residual as opposed to original tumor lesions with a margin of “no ink on tumor” regardless of unifocal or multifocal disease Exception: IBC
  10. 10. Tratamiento quirúrgico: manejo de la axila y tto neoadyuvante If > 3 sentinel nodes identified and negative or if clipped node and 1 or 2 additional nodes removed and negative Even if micromets residual cancer If cN2 at diagnosis: - Axillary disection - Regional nodal RT (regardeless response to NST)
  11. 11. Tratamiento RT adyuvante Following breast conserving surgery, whole breast irradiation remains the standard treatment recommendation for optimal outcomes The Panel recommended hypofractionated radiation treatment schedules as preferred for most patients after breast conservation [Whelan]. Two trials [RAPID, B-39] - equally low risks of local recurrence in selected women with low-risk breast cancer undergoing accelerated partial breast irradiation (APBI) compared with whole breast irradiation. - Less favorable cosmetic outcomes were seen after APBI - may be appropriate for carefully selected patients at low-risk of local recurrence
  12. 12. Tratamiento RT adyuvante: Elderly Older women might avoid radiation therapy after breast conserving surgery for stage 1 breast cancer as randomized trials have shown that post-surgical radiation therapy does not improve overall survival The Panel tended to favor radiation after breast conserving surgery in women age 70 who were otherwise in good health with substantial life-expectancy, as radiation therapy meaningfully lowers the risk of in-breast recurrence. However, the Panel recommended against radiation in the “oldest” of the elderly, age 80 or greater
  13. 13. Tratamiento RT adyuvante: Regional Node Irradiation RNI in cases of involvement of 4 or more axillary lymph nodes. In cases of 1 to 3 positive lymph nodes, RNI in cases with adverse prognostic factors : triple-negative, HER2, and luminal B cancers, and in women witihn residual disease after NST
  14. 14. Tratamiento RT adyuvante: post MT (PMRT) Postmastectomy radiation therapy to the chest wall and regional lymph nodes in cases of 4 or more positive nodes, or 1 to 3 positive nodes with triple-negative histology. Discrepancies: HER2+, ER+ with 1-3 nodes, or T>5cm NO recommended for T2N0 Same recommendations if inmmediate reconstruction (cosmesis impact) After NST: - PMRT if 1-3 residual nodes after NST - in cT3cN0 triple negative breast cancer, even if pCR
  15. 15. Role of endocrine therapy in tumors with low ER expression (less than 10%) - have a less favorable prognosis. - most contemporary clinical trials involving endocrine therapy limit enrollment to patients with tumors that are > 10% ER-positive. - many trials for triple negative disease exclude patients with tumors that have 1-10% staining ER staining. - general consensus that the benefits of endocrine therapy are lower or possibly absent when ER staining is 1-10%. However, without clinical data, the Panel could not identify a clear threshold for withholding endocrine therapy and many panelists recommended adjuvant endocrine therapy for tumors with > 1% ER expression [2]. Tratamiento adyuvante en ER+
  16. 16. Tratamiento adyuvante en ER+ Expert pathology RE, PR and proliferation levels serves as a surrogate for classification into more favorable Luminal A vs B cancers; however this assessments lack robust validation The Panel strongly endorsed the value of genomic assays in T1/T2 N0 T3 N0, and TxN1 (1 to 3 positive LN).
  17. 17. Tratamiento adyuvante en ER+
  18. 18. Tratamiento adyuvante en HER2 + y TN
  19. 19. - The Panel recommended that tumor infiltrating lymphocytes (TILs) be routinely characterized in triple negative breast cancer (TNBC) because of their prognostic value. However, data are inadequate to recommend TILs as a test to guide neo/adjuvant treatment choices in TNBC, as treatments are largely governed by anatomic stage. - Tumor PD-L1 or immune-cell PD-1 expression are recognized as markers that may predict benefit from immunotherapy treatment in advanced breast cancer. However, the Panel recommended against routine PD-L1 tumor or PD-1 immune cell testing in early stage TNBC, as current treatment algorithms are not based on such testing Tratamiento adyuvante en TN
  20. 20. Cáncer de mama precoz HER2+ > 2 cm y/o cN+ < 2 cm y cN0 NEOADYUVANCIA* - FECx3 > Docetaxel + Trastu + Pertu x 3 - ACx4 > Taxol + Trastu + Pertu x 12 semanas - Docetaxel + Carbo + Trastu + Pertu x 6 *Considerar Trastu + Pertu junto a antraciclinas y taxanos en tumores de alto riesgo **El uso de Pertuzumab en Adyuvancia está autorizada por la EMA pendiente de financiación (P&R) ***pCR: ausencia de carcinoma infiltrante en mama y axila CIRUGÍA pT < 2 cm y pN0 ADYUVANCIA Taxol x 12 + Trastu x18 ciclos CIRUGÍA no pCR*** pCR*** ADYUVANCIA TDM1 pN+ cN0 al diagnóstico cN+ al diagnóstico ADYUVANCIA Trastu + Pertu** x total 18 ciclos (más QT antras + taxanos si no neoadyuvancia) ADYUVANCIA Trastu x total 18 ciclos Algoritmo de elaboración propi
  21. 21. ESMO 2019 Cáncer de mama
  22. 22. KEYNOTE-522: pCR by Key Patient Subgroups pCR, % (n/N) Pembro + CT (n = 401) Placebo + CT (n = 201) Δ (95% CI) Disease stage IIA IIB IIIA IIIB 73.1 (133/182) 56.2 (68/121) 66.7 (40/60) 48.6 (18/37) 62.1 (54/87) 48.4 (30/62) 42.1 (16/38) 23.1 (3/13) 11.0 (-0.7 to 23.2) 7.8 (-7.4 to 22.8) 24.6 (4.3 to 43.1) 25.6 (-6.1 to 48.9) Lymph node involvement Negative Positive 64.9 (124/191) 64.8 (136/210) 58.6 (58/99) 44.1 (45/102) 6.3 (-5.3 to 18.2) 20.6 (8.9 to 39.1) PD-L1 expression CPS < 1 CPS ≥ 1 CPS ≥ 10 CPS ≥ 20 45.3 (29/64) 68.9 (230/334) 77.9 (162/208) 81.7 (103/126) 30.3 (10.33) 54.9 (90/164) 59.8 (55/92) 62.5 (40/64) 18.3 (-3.3 to 36.8) 14.2 (5.3 to 23.1) 17.5 (6.2 to 29.1) 18.5 (5.0 to 32.7) Chemotherapy exposure* Full exposure < Full exposure 69.7 (314/307) 51.1 (46/90) 55.3 (88/159) 35.7 (15/42) 14.4 (5.1 to 3.6) 15.4 (-3.0 to 32.1) Schmid. SABCS 2019. Abstr GS3-03 *Full exposure comprised paclitaxel weekly 10-12 doses, carboplatin weekly 10-12 doses or Q3W 4 doses, doxorubicin or epirubicin Q3W 4 doses, and cyclophosphamide Q3W 4 doses, regardless of exposure to pembrolizumab.
  23. 23. • Primary endpoint: IDFS • Secondary endpoints: IDFS with second non-breast primary cancers included, DFS, OS, RFI, DRFI, safety and HRQoL • Stratification factors: Chemotherapy regimen, HR status, nodal status, geographic region, Protocol version (A vs. B) Chemotherapy* + trastuzumab + placebo (n=2405) Chemotherapy* + trastuzumab + pertuzumab (n=2400) Randomisation and treatment within 8 weeks of surgery Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy Central confirmation of HER2 status (N = 4805) F O L L O W - U P 10 Y E A R S R S U R G E R Y * Standard anthracycline or non-anthracycline (TCH) regimens were allowed APHINITY Von Minckwitz G, et al. N Engl J Med 2017; 377:122–131 DRFI, distant relapse-free interval; HRQoL, health-related quality of life; RFI, relapse-free interval.
  24. 24. APHINITY: Clinical Benefit in Primary vs Secondary Analysis HR for IDFS (95% CI) Primary Analysis (mFU: 45.4 Mos) Updated Analysis (mFU: 74.1 Mos) ITT population 0.81 (0.66-1.00) 0.76 (0.64-0.91) Lymph node positive 0.77 (0.62-0.96) 0.72 (0.59-0.87) Lymph node negative 1.13 (0.68-1.86) 1.02 (0.69-1.53) Hormone receptor positive 0.86 (0.66-1.13) 0.73 (0.59-0.92) Hormone receptor negative 0.76 (0.56-1.04) 0.83 (0.63-1.10) IDFS at 6-Yr Pertuzumab, % Placebo, % Absolute Benefit, % (95% CI) ITT population 90.6 87.8 2.8 (1.0-4.6) Lymph node positive 87.9 83.4 4.5 (1.9-7.1) Lymph node negative 95.0 94.9 0.1 (-2.0-2.2) Hormone receptor positive 91.2 88.2 3.0 (0.8-5.2) Hormone receptor negative 89.5 87.0 2.5 (-0.7-5.6) Piccart. SABCS 2019. Abstr GS1-04
  25. 25. FeDeriCa: study design Tan. SABCS 2019. Abstr PD4-07 Primary objective: Non-inferiority of the pre-dose cycle 8 P serum trough [ ] within PH FDC SC vs P IV Secondary objectives: Non-inferiority of the pre-dose cycle 8 H serum trough [ ] , tpCR, safety
  26. 26. FeDeriCa: tpCR Tan. SABCS 2019. Abstr PD4-07
  27. 27. • Open-label, randomized phase III trial Atezolizumab 1200 mg Day 1 Q3W for 8 cycles + Carboplatin AUC2 + nab-Paclitaxel 125 mg/m2 Day 1, Day 8 Q3W; 8 cycles (n = 138) NeoTRIPaPDL1: Study Design Patients with HER2-/ER- /PgR- early, high-risk (T1cN1, T2N1, or T3N0) or locally advanced unilateral breast cancer* (N = 280) Carboplatin AUC2 + nab-Paclitaxel (125 mg/m2) Day 1, Day 8 Q3W; 8 cycles (n = 142) ▪ Primary endpoint: EFS at 5 yrs after randomization of last patient ▪ Key secondary endpoint: pCR rate ▪ Other secondary endpoints: tolerability; predictive biomarkers Gianni. SABCS 2019. Abstr GS3-04 Stratified by geographical area, disease stage (early, high risk vs locally advanced), PD-L1 expression (positive IC vs negative) *ER, PgR, HER2, and PD-L1 centrally assessed before randomization. Tumor and blood banked for correlative studies. Surgery followed by anthracycline regimen x 4 cycles per investigator choice
  28. 28. NeoTRIPaPDL1: pCR Rate (ITT) Overall pCR rate difference: 2.63%; odds ratio: 1.11 (95% CI: 0.69-1.79); P = .66 Gianni. SABCS 2019. Abstr GS3-04 Overall PD-L1 +ve PD-L1 -ve 60 50 40 30 20 10 0 43.5% 40.8% 51.9% 48.0% 32.2% 32.3% Early, HR Locally Advanced 44.9% 39.7% 42.0% 42.0% Carboplatin/nab-paclitaxel Atezolizumab + carboplatin/ nab-paclitaxel
  29. 29. NSABP B-42: Study Design Mamounas. Lancet Oncol. 2019;20(1):88. Mamounas. SABCS 2019. Abstr GS4-01 • Primary endpoint: DFS, second non-breast primary malignancy, or death from any cause (ITT) • Secondary endpoints: OS, BCFI, distant recurrence, osteoporotic fractures, arterial thrombotic events Postmenopausal pts with stage I-IIIA ER+ or PgR+ BC at diagnosis who were disease free after 5 yrs of endocrine therapy* (N = 3966) *Endocrine therapy defined as treatment with an AI or tamoxifen for ≤ 3 yrs followed by an AI to complete 5 yrs Stratification for pathologic nodal status (negative vs positive); prior adjuvant TAM (yes vs no); lowest BMD T-score in spine, hip, or femur (> -2.0 to ≤ - 2.0 SD) Letrozole 2.5 mg PO QD x 5 yrs (n = 1983) Placebo x 5 yrs (n = 1983)
  30. 30. NSABP B-42: DFS Mamounas. SABCS 2019. Abstr GS4-01 Analy sis Events, N HR (95% CI) P Value*LET PB O 7 yrs 292 339 0.85 (0.73- 0.999) .048 10 yrs 411 479 0.84 (0.74- 0.96) .011 *Statistical significance level for DFS set at .0418. 10-Yr DFSDFS(%) Yrs After Randomization PBO LET 1.0 0.8 0.6 0.4 0.2 0.0 76.1 % 72.1 % 10 39 4 39 4 0 19 53 19 50 2 18 15 18 20 4 16 45 16 62 6 14 17 14 67 8 11 80 12 25
  31. 31. CORALLEEN: Study design Postmenopausal Stage II-III, HR+/HER2- and PAM50 LumB Letrozole + Ribociclib TREATMENT S U R G E R Y PAM50 ROR-low 6 months N=106 AC –> Paclitaxel 1:1 Week 2 biopsy Gavilá. SABCS 2019. Abstr GS4-02
  32. 32. Chemotherapy n= 52 Ribociclib + letrozole n= 49 N (%) 95% CI N (%) 95% CI ROR-low 24 (46.1%) 32.9-61.5 23 (46.9%) 32.5-61.7 ROR-intermediate 16 (30.8%) 19.1-45.9 15 (30.6%) 18.2-45.4 ROR-high 11 (21.2%) 11.2-35.2 11 (22.5%) 11.8-36.7 Missing 1 (1.9%) NA NA NA Primary endpoint This presentation is the intellectual property of the author/presenter. Contact them at jgavila@fivo.org for permission to reprint and/or distribute San Antonio Breast Cancer Symposium®, December 10-14, 2019
  33. 33. San Antonio Breast Cancer Symposium®, December 10-14, 2019 Key secondary endpoints at surgery This presentation is the intellectual property of the author/presenter. Contact them at jgavila@fivo.org for permission to reprint and/or distribute Chemotherapy n= 52 Ribociclib + letrozole n= 49 N (%) 95% IC N (%) 95% IC ROR score median (IQR) 25 (12.0-45.0) 18 (12.0-35.0) Central Ki67 IHC median (IQR) 10 (3.0-20.0) 3 (1.0-8.0) RCB 0-1 rate 6 (11.8%) 4.5-27.8 3 (6.1%) 1.3-16.8 pCR rate 3 (5.8%) 1.4-16.6 0 (0%) 0-7.2 PEPI 0 9 (17.3%) 8.6-31.4 11 (22.4%) 11.7-36.6 1-3 24 (46.1%) 33.6-62.6 25 (51.0%) 36.3-65.6 ≥4 17 (32.7%) 21.2-48.7 13 (26.6%) 15.0-41.2 Missing 2 (3.9%) 0
  34. 34. Conclusiones • Neoadyuvancia como biomarcador para seleccionar tratamiento adyuvante / grupos de riesgo • Limitar la extensión de cirugía y RT • Inmunoterapia en Ca mama precoz TN: controvertido • Pertuzumab adyuvante: N+ • Nuevas formulaciones sc • TDM1 tras neoadyuvancia (no pCR) • Valor establecido de plataformas genómicas en enfermedad luminal • Neoadyuvancia hormonal + CDKi como reemplazo de QT • Adyuvancia hormonal extendida: seleccionar en grupos de riesgo (toxicidades/cumplimiento)

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