Impact of BMI on pathologic complete response (pcr) following neo adjuvant chemotherapy (NAC) for locally advanced breast cancer Rachna Raman, MD, MS Fellow physician University of Iowa hospitals and clinics
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Introduction
Neo adjuvant chemotherapy in breast cancer (NAC) Inoperable locally advanced Operable(IIA, IIB, III) high risk, if breast conservation desired (10-30% conversion rate) Breast conservation not an option after NAC for Inflammatory Breast cancer Offers the same survival advantage as adjuvant chemotherapy Provides prognostic information Wolmark et al. 2001; Van der Hage et al. 2001; Hennessy et al. 2005
Pathologic complete response (pcr) Definition: No evidence of invasive cancer in the breast or lymph nodes Significance - Suggested surrogate for long term outcomes (DFS and OS ) - Above possibly true only for HR-/HER2-, and HER2+ tumours -TNBC with pcr to NAC has the same prognosis as other subtypes - Pertuzumab first drug to be approved based on pcr data Untch M JCO 2012, Cortazar P Lancet 2014
Predictors of pcr Treatments Preoperative taxanes especially if partial clinical response with anthracyclines (in the range of 30%) Anti HER 2 therapy (> 60% with TCH+P) Clinical and histologic characteristics Age < 50 Earlier stage Non lobular histology Hormone receptor negative tumors Higher grade Triple negative HER 2 positive disease BMI?? Untch M JCO 2012 Bear HD JCO 2006 Schneeweiss A, Cancer Research 2011; 71(24 Suppl.):Abstract S5-6
Tumor propagating effects of obesity Increased tumor associated macrophages Metabolic perturbations - IGF-1, insulin resistance Altered pharmacokinetics Obesity associated chemoresistance mechanisms Impaired drug delivery Adipose tissue expansion - Direct tumor invasion and increase in tumor volume - protumorigenic cytokines Chronic state of inflammation - Cytokines - Fibrosis Lashinger LM Clin Pharmacol Ther 2014
Is BMI associated with response to NAC in breast cancer Study N Chemotherapy dosing information MDACC (2008) pcr pcr BMI< 25 vs >= 25 1169 No 15% OR = 0.67 (CI 0.45-0.99) Chinese (2012) 307 Yes, no BSA cap T + Carbo only 17% OR= 0.454 (CI 0.22-0.93 MDACC (2012) German (2015) Iowa BMER (2015) Matched case control (67 with pcr c/t 67 without) Pooled from 8 German trials (8872) No NA OR = 0.33 (CI 0.13-0.85) * Association only with overweight but not obese) No, 3/8 studies capped at a BSA of 2 87 Yes, no BSA cap - - 21% OR = 0.91 (0.73-1.15)
Summary: BMI, NAC and pcr The association between BMI and pcr following NAC remains undefined Retrospective analysis suggest a detrimental impact of BMI on pcr Most studies do not account for actual chemotherapy doses delivered. The largest (German) pooled analysis is worth discussing
The German pooled analysis BMI and pcr On further subgroup analysis, the detrimental effect of increasing BMI on pcr was significant for HR+HER2 negative tumors only
Iowa BMER study objectives Study question Does BMI at the initiation of neoadjuvant chemotherapy impact the odds of achieving a pcr at the time of Definitive surgery? Primary objective Determine the odds of achieving a pcr in the obese/overweight compared to the normal/underweight women Secondary objectives Determine the odds of achieving a pcr in the two BMI groups when adjusted for cumulative chemotherapy dose delivered Determine the odds of achieving a pcr in the two BMI groups adjusting for the breast cancer subtype
Iowa BMER study: Methods Patients - All patients enrolled in the Iowa BMER - Age >= 18 years - Received at least 1 cycle of intended neoadjuvant chemotherapy - Baseline weight and height available - Completed definitive surgery by March 2015 - Dose per cycle per chemo available Definitions - Obese overweight: BMI >= 25 - pcr: No residual invasive cancer in the breast or lymph nodes - Breast cancer subtypes: Luminal A: ER+ & PR+/ HER2 neg, ER or PER pos/ HER2 neg, HER 2 +, Triple negative - Dose reduction: Any decrease from the total intended dose
Iowa BMER study: Methods Treatments: TAC, TCH, FEC-> D, AC-T with or without a HER 2 blocking agents (H, H + P or H+ L) Dosing - Dose reduction estimates: Included all but the HER 2 blocking agents - Cumulative dose delivered: Total delivered dose per cycle x number of cycles - Cumulative expected dose: Total expected dose per cycle x expected number of cycles for each regimen Values calculated separately for taxanes and non taxanes. Statistical analysis: Chi-square tests and logistic regression models used
Results
Patient characteristics BMI 2: Overweight- Covariate Level 1: Normal N=36 Obese N=51 Stage N(%) I-II 27 (75) 35 (68.6) III-IV 9 (25) 16 (31.4) EE Grade N(%) G1-2 14 (38.9) 24 (47.1) G3 22 (61.1) 27 (52.9) ER N(%) Negative 20 (55.6) 21 (41.2) Positive 16 (44.4) 30 (58.8) PR N(%) Negative 20 (55.6) 25 (49) Positive 16 (44.4) 26 (51) Her2+ N(%) Negative 25 (71.4) 39 (76.5) Positive 10 (28.6) 12 (23.5) ER+PR+ N(%) No 25 (71.4) 31 (60.8) Yes 10 (28.6) 20 (39.2) ER+PR- N(%) No 34 (97.1) 47 (92.2) Yes 1 (2.9) 4 (7.8) Triple Negative No 23 (65.7) 38 (74.5) N(%) Yes 12 (34.3) 13 (25.5) Type of Surgery Lumpectomy 10 (27.8) 25 (49) N(%) Mastectomy 26 (72.2) 26 (51) Age (Median) 42.83 50.59
Predictors of pcr in the Iowa BMER Odds of Not Achieving a PCR Covariate Level N Odds Ratio 95%CI Low 95%CI Up OR P- value Menopause Yes 34 1.20 0.45 3.19 0.72 BMI No 46 - - - - Overweight -Obese 50 1.96 0.78 4.97 0.15 Normal 34 - - - - Stage III-IV 25 6.57 1.58 27.28 <.01 I-II 61 - - - - Grade G1-2 37 3.66 1.31 10.20 0.01 G3 49 - - - - Her2n No 64 1.58 0.56 4.44 0.38 Yes 21 - - - - TNBC Yes 25 0.55 0.21 1.46 0.23 No 60 - - - - ER+PR+ Yes 30 3.96 1.25 12.49 0.02 No 55 - - - - TaxRed Y 27 1.10 0.41 2.96 0.84 N 59 - - - - Non TaxRed Y 17 1.08 0.34 3.40 0.90 N 69 - - - - Age Diag 86 1.02 0.98 1.07 0.30
Results Association between BMI category and NAC dose reduction Dose reduced Taxane 30 (83%) Non taxane 28 (78%) BMI < 25 (n= 36) BMI >= 25 (n= 51) P value No Yes No Yes 6(17%) 29 (57%) 22(43%) < 0.01 8 (22%) 40 (78%) 11 (22%) 0.94
Results: Reasons for Taxane dose reduction Adverse event Docetaxel (n = 12) Paclitaxel (14) Neuropathy 6 4 Myelosuppresion and grade 3 infections 2 4 LFT abnormalities 1 1 Grade 3 Nausea/emesis Others (allergic, patient preference, unrelated stroke) 0 2 3 3
Impact of taxane dose reduction on pcr by BMI category Normal Overweight-Obese Taxane reduction No pcr pcr No pcr pcr No 19(63%) 11(37%) 20(69%) 9(31%) Yes 2(33%) 4(67%) 18(82%) 4(28%) Interaction between BMI and taxane dose reduction on pcr : p=0.10
Discussion Findings and limitations Taxanes Future directions
Conclusions The odds of attaining a pcr are higher with higher grade, hormone receptor negative and early stage disease Being overweight obese was not found to be associated with the odds of achieving a pcr following NAC, however a trend towards decreased odds were noted Overweight obese are significantly more likely to have taxane doses reduced during NAC due to higher rate of adverse events BMI may modify the effects of taxane dose reduction on the likelihood of achieving a pcr The association between BMI, chemotherapy dosing and pcr must be examined in a larger cohort