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Neoadjuvant therapy decisions in non-Her2 breast cancer 10/4/16 Objectives • • • • • • • Rationale for neoadjuvant chemo Patient selection Chemo regimens Surgical considerations- breast and axilla Special populations- triple neg, her-2 pos, inflammatory Neoadjuvant endocrine Rx considerations Ongoing trials WHY and WHO? • Why neoadjuvant chemotherapy needs to be given? • Who are ideal candidates? Rationale • • • • • Tumor shrinkage Down stage axilla Efficacy of chemo (response adjusted approach) Prognosticate- pCR Research- tumor samples while on chemo to identify tumor and patient specific biomarkers correlating with response • Allows time for genetic testing and plan reconstruction Patient selection • • • • • Locally advanced/inflammatory High tumor to breast ratio Tumor subtypes Contraindication to upfront surgery such as pregnancy Inappropriate pts- diffuse disease, extensive in-situ carcinoma, tumors not readily palpable • DO NOT give neoadjuvant chemo to patients that you are unsure about giving chemo adjuvantly Patient-1 • 42 y/o female with HTN presents with new Rt breast mass, no other symptoms reported. Imaging confirms 4.2 cm mass in the Rt breast, normal axillary contents on US. Biopsy showed IDC, grade III, ER 100%. PR 20%, Her2 neg. She desires breast conservation if possible so she is referred to you for neoadjuvant chemo. What are the next steps? What would you give her? Pre-treatment evaluation • • • • • Tumor biopsy and clipping Nodal eval- bx of abnormal nodes ? Pre-op SLNBx (radiotherapy decisions may be helped) FNR of post-chemo SLNBx Routine imaging to assess systemic disease – symptomatic pts or bulky disease Chemotherapy • NCCN: Regimens recommended in adjuvant setting may be considered in the pre-operative setting. • Preferred regimens: ddAC ddPac, ddAC weekly Pac TC • Other regimens: AC, EC, CMF, ACDoc/Pac, TAC, FEC or FAC followed by taxane NSABP B-18 and NSABP B-27 • B18: N = 1523 pts with operable cancer randomized to preoperative AC x4 vs post-operative AC x4 • B27: N = 2411 pts with operable cancer randomized to: pre-op AC x4 Sx pre-op ACx4 pre-op Doc x4 Sx pre-op ACx4 Sx post-op Doc x4 Fischer et al. J Clin Oncol 1997 Bear et al. J Clin Oncol 2006 OS, DFS and RFI for Protocol B-18 and B-27 Rastogi et al. JCO 2008;26:778-785 Patients with pCR in group 2 (pre-op AC Doc) versus groups 1 and 3 Harry D. Bear et al. JCO 2006;24:2019-2027 Survival by pCR in NSABP-B18 and NSABP-B27 Priya Rastogi et al. JCO 2008;26:778-785 Refining Taxane therapy: E1199 • Phase III adjuvant trial with N-4950, node positive or high risk node negative patients • Treatment arms: AC x4 every 3 weeks followed by Pac x4 every 3 weeks (std arm) • Comparison arms: weekly Pac x 12, weekly Doc x 12 Doc every 3 weeks x4 Sparano et al. N Engl J Med 2008 E1199: DFS curves Sparano JA et al. N Engl J Med 2008;358:1663-1671 Sparano et al. N Engl J Med 2008 E1199: OS curves Sparano JA et al. N Engl J Med 2008;358:1663-1671 Sparano et al. N Engl J Med 2008 TE1199: Toxicity profile Effects of Paclitaxel and Docetaxel. Sparano JA et al. N Engl J Med 2008;358:1663-1671 Sparano et al. N Engl J Med 2008 E1199: Conclusions • Weekly paclitaxel after AC improves disease-free and overall survival in women with breast cancer • It comes at a price of increased neurotoxicity (grades 2,3 and 4- 27% vs 20%) Sparano et al. N Engl J Med 2008 Patient-2 • 74 y/o female with seasonal allergies present with a large mass in the left axilla. She is relatively active and does yoga and pilates four times a week. Imaging showed 2.5 cm mass in the left breast with several abnormal axillary nodes. Biopsy showed invasive carcinoma, grade II, ER 80%, PR neg, her-2 neg with mets to axilla. She underwent PET scan which was neg for systemic disease. She is referred for neoadjuvant chemotherapy. • Would you offer neoadjuvant chemo and if so what chemo regimen would you pick for her? Dose density: CALGB- 9741 Treatment schema Citron et al. J Clin Oncol. 2003 (A) Disease-free survival by dose density; (B) overall survival by dose density DFS was significantly prolonged for the dose-dense regimens compared with the every-3-weeks regimens (risk ratio [RR] = 0.74; P = .010). OS was significantly prolonged in the dose-dense regimens (RR = 0.69; P = .013) This dose-density effect remained significant even after adjusting for number of positive nodes, tumor size, menopausal status, and ER status. Citron et al. J Clin Oncol. 2003 Patient-3 • 58 y/o female with 2.8 cm breast mass and positive nodes, triple neg disease is receiving neoadjuvant chemotherapy. She has completed dose dense AC and has tolerated it fairly. She has had some tumor shrinkage so far clinically. She is starting weekly Taxol today but as soon as she is started, she starts c/o chest tightness, difficulty breathing and feeling lightheaded. Her HR is 122 and she is hypoxic at 87% on RA, BP is normal. She is given additional hydrocortisone and benadryl. After 30 minutes, she is feeling better and her vitals return to normal. • What would you do? GBG 69 – GeparSepto: Pac Vs Nab-Pac Untch et al. Lancet 2016 GBG 69 - GeparSepto ypT0N0 275 TNBC: • 48% vs 26% (p<0.001) • HR 2.69 (1.62-4.46) Neuropathy worse with nab-P • Gr 3+ 14% vs 3% • D/c rate 17% vs 6% Untch et al. Lancet 2016 ETNA: Evaluating Treatment with Neoadjuvant Nab Paclitaxel • 695 patients with centrally confirmed HER2 negative breast cancer • Randomized to paclitaxel (90 mg/m2) or nab-paclitaxel (125 mg/m2) • Given weekly: 3 weeks on, one week off x 4 cycles • Followed by 4 cycles of anthracycline regimen of choice, then surgery • Primary endpoint: pCR (absence of invasive disease in breast and nodes) • pCR was similar between the two arms Gianni et al, J Clin Oncol 34, 2016 (suppl; abstr 502) ETNA Trial and Implications • Why is this different? • 16 week exposure rather than 12 • Dose per week lower: 125 mg/m2 vs 93.75 mg/m2 • Clinical Implications • Await DFS data from GeparSepto • Caution about neuropathy which is clearly increased • No need for steroids may be an advantage with immunotherapy Patient-4 • 40 y/o female was found to have a 3.5 cm mass in Rt breast upon her first routine mammogram. US showed one abnormal node which showed enhancement on MRI, biopsy confirmed positive node. Biopsy showed IDC, high grade, triple negative. Her sister was diagnosed with breast cancer at age 44 and is doing well. • What are your recommendations? • Patients who became BCS candidates with neoadjuvant therapy 55% versus 41% , p= NS Role of Neoadjuvant Platinum in TNBC: Randomized Trials Primary end-point: pCR rates Study No Backbone Regimen No Carbo Carboplatin GeparSixto* 315 Weekly paclitaxel + liposomal dox + bev 38% 59% P< 0.05 C40603** 433 Sequential weekly paclitaxel – AC +/- bev 41% 54% P=0.0029 Tamura et al 75 Sequential weekly pacl+/- Carb AUC5 - CEF 26% 62% Alba et al 94 EC – Doc +/- Carbo AUC6 30% 30% *3-yr DFS from Gepar-Sixto 86% vs 76% favoring carboplatin reported at SABCS 2015 **Patients who became BCS candidates with neoadjuvant therapy 55% versus 41% , p= NS Von Minckwitz et al. Lancet Oncol 2014; Sikov et al. JCO 2015; Alba et al. BRCT 2012; Tamura et al. ASCO 2014, Abstract 1107 ISPY-2: Adaptive randomization of Veliparib-carboplatin • Adaptive trial design: - minimize the exposure of patients to inactive agents - detect more active regimens sooner Adding veliparib and carboplatin to standard therapy improved outcome in triple-negative breast cancer. Rugo et al. N Engl J Med. 2016 Trial Design Rugo HS et al. N Engl J Med 2016;375:23-34 Rugo et al. N Engl J Med. 2016 Estimated Rate of pCR with Veliparib–Carboplatin versus the Concurrent HER2-Negative Control. Rugo HS et al. N Engl J Med 2016;375:23-34 Rugo et al. N Engl J Med. 2016 Final Predictive Probabilities. Rugo HS et al. N Engl J Med 2016;375:23-34 Rugo et al. N Engl J Med. 2016 Selected Adverse Events and Toxic Effects. Rugo et al. N Engl J Med. 2016 2016;375:23-34 Chemotherapy conclusions • Pre-op AC is equivalent to pos-op AC • Addition of pre-op Doc to pre-op AC improves pCR which translates in to improved survival • Pac given every week is better than every 3 weeks in terms of DFS and OS but is associated with slightly increase neurotoxicity • Dose density improves DFS and OS in breast cancer at no added toxicity Chemotherapy conclusions • TC regimen is strictly studied in adjuvant setting and need to use caution before using it pre-operatively • Substitution of Pac with Abraxane is still premature till DFS and OS data is available • Addition of carboplatin may be considered in TNBC, particularly those with inadequate response to AC • Other agents tested for NACT- gemcitabine and capecitabine, no improvement in pCR or breast conservation Assessment of tumor response • Clinical exam through chemo every 2-4 weeks (neoadjuvant endocrine therapy every 4-8 weeks) • US/MRI during treatment only is progression suspected • Mammogram and MRI after chemo • Discordance between clinical exam, imaging and path findings can be seen due to variable patterns of tumor response Post-chemo nodal evaluation Clinically negative nodes before NACT: SLNbx after NACT Neg No further axillary surgery Pos If 1-2 LN then ALND or nodal XRT If >=3 LN then ALND Clinically positive nodes before NACT: Pos ALND Clinical response to NACT Neg Neg No more axillary Sx Pos ALND SLNbx Patient- 5 and 6 • 42 y/o female with 4 cm mass and one palpable node with biopsy prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your next step? • 76 y/o female with 4 cm mass and one palpable node with biopsy prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your next step? • How would you approach these patients? Are your recommendations same for both? • Would you give neoadjuvant therapy or send them to surgery first? Patient- 5 and 6 • 42 y/o female with 4 cm mass and one palpable node with biopsy prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your next step? • 76 y/o female with 4 cm mass and one palpable node with biopsy prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your next step? • How would you approach these patients? Are your recommendations same for both? • Would you give neoadjuvant therapy or send them to surgery first? • What if the surgeon ordered an oncotype and it was 10? Neoadjuvant endocrine therapy Study No Backbone Regimen RR Note Russian trial 239 AT x4 Vs Anastrozole/Exemestane 64% both BCS rates: 33% vs 24% P= 0.058 GIECAM 95 EC x4Doc x4 Vs Exemestane for 24 weeks 66% vs 48% P= 0.075 favor CT Low Ki-67 63% vs 58% P= 0.74 GEICAM premenopausal 51 CT-24 and HT-27 75% vs 44% P= 0.027 Exploratory unplanned analysis Semiglazov et al. Cancer 2007 Alba et al. Ann Oncol. 2012 Neoadjuvant endocrine therapy • Neoadjuvant endocrine therapy currently restricted to postmenopausal patients • Neoadjuvant endocrine therapy approach should be considered investigational for premenopausal women. • pCR uncommonly seen with either chemo or endocrine therapy, usual duration is 4-6 months so is pCR a good end-point for HR + breast cancer? • PEPI takes into account tumor and nodal stage, level of ER expression, and Ki67 following neoadjuvant endocrine therapy; and measurement of Ki67 before and during treatment • AI better than Tam in terms of RR and rates of breast conserving surgery, all AIs have similar clinical response rates Inflammatory breast cancer • Dx: rapid onset or erythema/peau d’orange, duration < 6 months, erythema occupying at least third of the breast & path confirmation of cancer • Staging/evaluation similar to locally advanced, third present with distant mets • NACT usually with ACT based on data in locally advanced tumors, add Traz/Per for her-2 pos tumors • XRT is given to all patients regardless of the surgery or response to NACT Operable NACT Inoperable Mastectomy + ALND Change chemo Pre-op XRT if inadequate response Future directions • Additional chemotherapy adjuvantly if inadequate response to NACT • Neoadjuvant endocrine therapy trials • Neoadjuvant CDK4/6 inhibitors • Platinum adjuvantly for inadequate response to NACT in TNBC • PARP inhibitors in TNBC and BRCAm breast cancerneoadjuvant and adjuvant settings • Neoadjuvant oncotype to guide therapy decisions CREATE-X: A Phase III Trial of Adjuvant Capecitabine in HER2-Negative BC with Pathologic Residual Invasive Disease After NACT Capecitabine Control HR (p-value) 2-year DFS rate 87.3% 80.5% 0.688 (0.001) 2-year OS rate 96.2% 93.9% 0.658 (0.086) Lee S-J et al. San Antonio Breast Cancer Symposium 2015;Abstract S107. ALTERNATE: Phase III trial of Fulvestrant and/or Anastrozole in postmenopausal women with stage II-III breast cancer undergoing surgery Estimated enrollment: 2820 patients Anastrozole Eligibility: T2-T4, any N, M0 pts with invasive breast cancer having PS 0-2 R Fulvestrant Anastrozole+ Fulvestrant Primary endpoints: Rates of endocrine resistance, recurrence free survival and pCR Secondary endpoint: post-treatment PEPI scores an its correlation with RFS and pCR if patient gets off study and gets chemo neoMONARCH: A Phase II Neoadjuvant Trial of Abemaciclib or Anastrozole Alone or the Combination Trial Identifier: NCT02441946 Enrollment: 148 (Closed) Abemaciclib Eligibility • Postmenopausal • HR+/HER2-negative breast adenocarcinoma • Clinical Stage I (≥1 cm), Stage II, Stage IIIA or IIIB R Anastrozole After day 14 all pts get the combination for 14 weeks Abemaciclib + anastrozole Primary endpoint: Change in Ki-67 levels between baseline and after 2 weeks of therapy www.clinicaltrials.gov, September 2016. EA1131 Trial Design Pre-Registration Stage II/III TNBC§ Primary Endpoint: - DFS in patients with basal-like TNBC Neoadjuvant Chemotherapy* Secondary Endpoints: - OS - RFS Stratification factors: 1) Disease stage at diagnosis (II or III) 2) Residual cancer burden after NAC (1~3 cm or >3 cm) 3) Platinum agent choice (cisplatin or carboplatin) 4) Anthracycline exposure (yes or no) Definitive surgery Residual cancer ≥1 cm Within 48 days Cisplatin 75 mg/m2 Registration Basal-like Randomization Tissue collection PAM50 analysis OR Carboplatin AUC 6 Q3W x 4 doses (1:1) Within 84 days Radiotherapy (when applicable) should be completed prior to protocol platinum therapy §TNBC: ER/PR classified locally as negative, or Allred score ≤ 2, or < 5% weakly positive staining *Taxane +/- Anthracycline based; platinum agents not allowed (physician’s choice) Observation Brightness trial Eligibility: N = 624 Neoadjuvant chemotherapy for Early stage TNBC Veliparib + Carboplatin + Paclitaxel AC R Placebo + Carboplatin + Paclitaxel AC Placebo + Placebo+ Paclitaxel AC www.clinicaltrials.gov, September 2016 OlympiA: OLaparib in Adjuvant BRCAm breast cancer Germline mutation carriers Olaparib 300 mg bd 12 months duration IDFS R 1:1 Double blind N = 1,320 Post adjuvant gBRCA TNBC T2 or N+ Placebo 12 month duration Distant DFS; OS Post neoadjuvant gBRCA TNBC, Non-PathCR pts Neoadjuvant HT or CT based on Oncotype scores Trial Identifier: NCT01293032 – Pilot study Enrollment: 64 (Closed) Eligibility • Pre and postmenopausal • HR+/HER2-negative invasive breast cancer • Primary tumor > 2cm, stages II and III O N C O T Y P E RS < 11 Hormone therapy RS 11-25 RS> 25 Chemotherapy www.clinicaltrials.gov, September 2016. CT R HT October is breast cancer awareness month