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, ACDoc/Pac, TAC, FEC or FAC followed by taxane

NSABP B-18 and NSABP B-27 B18: N = 1523 pts with operable cancer randomized to pre-operative 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 Pathologic tumor response at the time of surgery by treatment arm. *P < .0001 for testing percentage of patients with pathologic complete response in group 2 (after doxorubicin and cyclophosphamide [AC] plus docetaxel) versus groups 1 and 3 combined (after AC), adjusted for age, clinical tumor size, and clinical nodal status. DCIS, ductal carcinoma-in-situ. 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

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 et al. N Engl J Med 2008 Sparano JA et al. N Engl J Med 2008;358:1663-1671 Sparano et al. N Engl J Med 2008

Effects of Paclitaxel and Docetaxel. TE1199: Toxicity profile Effects of Paclitaxel and Docetaxel. Table 2 Toxic 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

E1199 : 10-year DFS & OS N = 1025 pts DFS TNBC OS TNBC P3 59% P1 69% HR 0.69 OS TNBC P3 66% P1 75% No improvement DFS or OS TNBC With D3 Sparano J. SABCS 2014, abst S3-03

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. DFS was significantly prolonged for the dose-dense regimens (II and IV) compared with the every-3-weeks regimens (I and III; risk ratio [RR] = 0.74; P = .010). This dose-density effect remained statistically significant even after adjusting for number of positive nodes, tumor size, menopausal status, and tumor 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 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% ypT0N0 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% *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 et al. N Engl J Med. 2016 Figure 1 Trial Design. Panel A shows the steps in the adaptive process of the trial. When new patients are enrolled, their cancer subtypes are assessed. As patients undergo randomization, their outcomes are used to update the Bayesian covariate-adjusted model that computes the predictive probability of success in phase 3 with regard to each biomarker signature. Prespecified termination rules are applied for each experimental group to determine whether the regimen should be stopped for futility, moved out of phase 2, or continue, adding on additional experimental groups, as permitted by ongoing patient enrollment. As the trial continues, for each experimental group, the probability of the superiority of each experimental regimen over the control within each subtype is updated, and the randomization probabilities for each subtype into the various experimental groups are adapted (such that new patients entering the trial will be more likely to be randomly assigned to an agent that shows activity within their cancer subtype). Panel B shows the steps involved in the enrollment, randomization, and treatment process. First, patients are screened for eligibility. Eligible patients undergo adaptive randomization and are assigned to 12 weekly cycles of paclitaxel (and trastuzumab, if the patient has human epidermal growth factor receptor 2 [HER2]–positive disease) alone (control) or in combination with one of several experimental agents, followed by four cycles of doxorubicin–cyclophosphamide, with serial biomarkers assessed over the course of their therapy by means of biopsies, blood draws, and magnetic resonance imaging (MRI). Only patients with HER2-negative disease were randomly assigned to the veliparib–carboplatin group. Panel C shows the details regarding the screening, randomization, and treatment of the patients in the veliparib–carboplatin group and its concurrent control group. Only patients with HER2-negative disease were eligible for random assignment to the veliparib–carboplatin group. Patients were categorized as having received the assigned intervention if they received at least one dose of experimental or control therapy. 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. Figure 2 Estimated Rate of Pathological Complete Response with Veliparib–Carboplatin versus the Concurrent HER2-Negative Control. Panel A shows the probability distribution for all patients with HER2-negative disease, Panel B the probability distribution for patients with hormone-receptor–negative and HER2-negative (triple-negative) disease, and Panel C the probability distribution for patients with hormone-receptor–positive and HER2-negative disease. The red curves represent patients treated with veliparib–carboplatin plus paclitaxel followed by doxorubicin–cyclophosphamide, and the blue curves represent concurrent controls. The corresponding 95% probability intervals (PIs) (represented by the arrows) are shown for each. The mean of each distribution is the estimated rate of pathological complete response. Rugo HS et al. N Engl J Med 2016;375:23-34 Rugo et al. N Engl J Med. 2016

Final Predictive Probabilities. Table 2 Final Predictive Probabilities. Rugo et al. N Engl J Med. 2016 Rugo HS et al. N Engl J Med 2016;375:23-34

Selected Adverse Events and Toxic Effects. Table 3 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: Neg No further axillary surgery SLNbx after NACT If 1-2 LN then ALND or nodal XRT If >=3 LN then ALND Pos Clinically positive nodes before NACT: Pos ALND No more axillary Sx Clinical response to NACT Neg Neg SLNbx Pos ALND

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 x4Doc 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 ACT 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 Mastectomy + ALND Operable NACT Pre-op XRT if inadequate response Inoperable Change chemo

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 cancer- neoadjuvant 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.

Anastrozole+ Fulvestrant 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

Abemaciclib + anastrozole 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 After day 14 all pts get the combination for 14 weeks Anastrozole R 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 Basal-like Stage II/III TNBC§ Neoadjuvant §TNBC: ER/PR classified locally as negative, or Allred score ≤ 2, or < 5% weakly positive staining *Taxane +/- Anthracycline based; platinum agents not allowed Primary Endpoint: DFS in patients with basal-like TNBC Secondary Endpoints: OS RFS Stratification factors: Disease stage at diagnosis (II or III) Residual cancer burden after NAC (1~3 cm or >3 cm) Platinum agent choice (cisplatin or carboplatin) Anthracycline exposure (yes or no) Tissue collection PAM50 analysis Observation Cisplatin 75 mg/m2 OR Carboplatin AUC 6 Q3W x 4 doses (physician’s choice) (1:1) Registration Randomization Within 48 days Within 84 days Residual cancer ≥1 cm Definitive surgery Neoadjuvant Chemotherapy* Pre-Registration Basal-like Radiotherapy (when applicable) should be completed prior to protocol platinum therapy Stage II/III TNBC§ EA1131 Trial Design

Brightness trial R Veliparib + Carboplatin + Paclitaxel  AC Eligibility: N = 624 Neoadjuvant chemotherapy for Early stage TNBC R Placebo + Carboplatin + Paclitaxel  AC Placebo + Placebo+ Paclitaxel  AC www.clinicaltrials.gov, September 2016

OlympiA: OLaparib in Adjuvant BRCAm breast cancer Germline mutation carriers Post neoadjuvant gBRCA TNBC, Non-PathCR pts Olaparib 300 mg bd 12 months duration R IDFS Distant DFS; OS Placebo 12 month duration 1:1 Double blind N = 1,320 Post adjuvant gBRCA TNBC T2 or N+

Neoadjuvant HT or CT based on Oncotype scores Trial Identifier: NCT01293032 – Pilot study Enrollment: 64 (Closed) RS < 11 Hormone therapy ONCOTYPE Eligibility Pre and postmenopausal HR+/HER2-negative invasive breast cancer Primary tumor > 2cm, stages II and III CT RS 11-25 R HT RS> 25 Chemotherapy www.clinicaltrials.gov, September 2016.

October is breast cancer awareness month