Lower Rates Of Pathologic Complete Response Research Articles

Differences in the immune microenvironment and genomic characteristics of TNBC in African American women compared to other races.

e13028 Background: African American (AA) women are more likely to be diagnosed with triple negative breast cancer (TNBC) compared to other races and have lower pathologic complete response rate to neoadjuvant therapy. Our goal was to assess differences in the immune microenvironment and genomic characteristics of TNBC by race using the TCGA data set. Methods: We compared the expression levels of 13 previously reported immune metagenes (CTL, Mphages, MHC1, Tregs, IF1, NK, STAT1, MHC2, Giam, Tfh, Tinh, Tstim, LCK), histologic tumor infiltrating lymphocyte (TIL) count and overall mutational load, neoantigen load, clonal heterogeneity assessed using the MATH score, amplification and deletion loads of between AA (n = 58) and non-AA TNBC (n = 114). Data was downloaded from the TCGA website, immune metagene expression and MATH scores were calculated as previously reported. Distributions between cohorts were compared using the Mann-Whitney U-test. Results: Among the immune metagenes only the cytotoxic T cell (CTL) metagene showed lower expression in AA patients (3.64 versus 4.08, unadjusted p = 0.046). TIL count was available in 51 of 58 AA and 91 of 114 of non-AA cases, and no significant difference was observed between the racial groups (p = 0.55). We also did not observe statistically significant differences in the mutational load (p = 0.36), neoantigen load (p = 0.38), clonal heterogeneity represented by the MATH score (p = 0.54), and amplification and deletion loads (p = 0.23 and 0.83 respectively) between the two TNBC race groups. We also assess the expression distribution of the immune signatures in an independent Affymetrix gene expression dataset including 40 AA and 323 non-AA patients with TNBC. Similar to the TCGA, there were no significant race differences in the immune signatures, including in the CTL metagene. Conclusions: These results suggest that the differences in prevalence and treatment response seen between TNBC in AA and non-AA patients are unlikely to be due to differences in the immune microenvironment and the genomic landscape of TNBC. However, more subtle comparison in the immune biology of these cancers can only be studies with more focused methods.

Systemic Inflammatory Response After Preoperative Chemoradiotherapy Can Affect Oncologic Outcomes in Locally Advanced Rectal Cancer.

Systemic inflammatory response (SIR) has been reported to be an important determinant of disease progression and survival in patients with colorectal cancer. This study investigated the prognostic relevance of changes in the platelet count on survival and the predictive value of changes in platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) on the pathological tumor response to preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). From 2006 to 2015, 291 consecutive patients with LARC who were treated with preoperative CRT followed by curative surgery at the Kyungpook National University Medical Center (Daegu, Korea) were retrospectively analyzed. A cut-off value of 370×103/μl for the platelet count was used and a PLR ≥235 was defined as high. Any change in the PLR or NLR was calculated based on subtracting the pre-CRT PLR or NLR from the post-CRT values. A total of 17.5% patients had stage II and 82.5% had stage III LARC. Initially high NLR and PLR were significantly associated with poor clinical outcomes. Patients who maintained a high platelet count after CRT also had an advanced pathological stage (p=0.028), low pathological complete response rate (p=0.048), and high relapse rate (p=0.021). For patients with an initially low PLR, the multiple logistic regression analysis revealed that a high PLR change (odds ratio (OR)=2.301, 95% confidence interval (CI)=1.269-4.174; p=0.006) and clinical stage II compared to stage III (OR=1.878, 95% CI=1.231-2.865; p=0.003) were significant independent markers predictive of a good response to CRT. The present results suggest that platelet and PLR change after preoperative CRT, along with the initial platelet count, can be used as prognostic and predictive markers for the oncological outcomes in patients with LARC.

Areca nut is associated with younger age of diagnosis, poor chemoradiotherapy response, and shorter overall survival in esophageal squamous cell carcinoma.

ObjectiveAreca nut chewing is carcinogenic to humans. However, little is known about the impact of areca nut chewing on esophageal squamous cell carcinoma (ESCC).MethodsWe retrospectively reviewed 286 ESCC patients who received surgery or preoperative chemoradiotherapy followed by surgery at our institution. Background characteristics including areca nut chewing history were analyzed. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine ESCC model was used to test the impact of arecoline, a main constituent of areca nut, on ESCC.ResultsCompared to patients without areca nut chewing history, patients with areca nut chewing history had overall a younger age of onset (Mean age: 56.75 versus 52.68 yrs, P<0.001) and significantly worse overall survival than those without areca nut chewing history (P = 0.026). Among patients who received surgery, the overall survival rates were not significantly different between those with or without areca nut chewing history. Among patients who received preoperative chemoradiotherapy followed by surgery, those with areca nut chewing history had a significantly lower pathologic complete response rate (P = 0.002) and lower overall survival rate (P = 0.002) than those without. In the murine ESCC model, the incidence of esophageal invasive squamous cell carcinoma was 40% in mice exposed to concomitant 4-NQO and arecoline treatment for 8 weeks and 6% in mice exposed to 4-NQO only for 8 weeks (P = 0.037).ConclusionsOur results indicate that areca nut chewing history is significantly associated with younger age of onset, poor response to chemoradiotherapy, and shorter overall survival in ESCC patients. Arecoline, a main constituent of areca nut, accelerates esophageal tumorigenesis in the 4-NQO-induced murine ESCC model.

Abstract P1-09-01: African American women have lower pathologic complete response rates to neoadjuvant chemotherapy compared to white women for triple negative and HER 2 positive breast cancer

Abstract Introduction Although racial disparities in breast cancer treatment have been well documented, data regarding differences in response to neoadjuvant chemotherapy are few. In 2010 the National Cancer Database (NCDB) included a new variable, documenting pathologic complete response (pCR) after neoadjuvant chemotherapy. The purpose of this study was to explore racial differences in the rates of pCR by molecular subtype. Methods The NCDB was queried to identify women diagnosed with invasive, stage 1-3 breast cancer in 2010 -2011 who received neoadjuvant chemotherapy. Univariate and multivariate logistic regression was performed to determine factors associated with likelihood of pCR. Results Out of 278,815 patients with known race and ethnicity, 27,300 (10%) received neoadjuvant chemotherapy. Of 17,970 where the outcome was known, 5,944 (33%) had a pCR. As seen in the table, there were no differences in response rate for ER/PR+ tumors, but compared to whites, non-hispanic black women had a lower rate of pCR for ER/PR- Her2+ and triple negative tumors. This difference persisted when adjusted for patient age, clinical T stage, clinical N stage, histology, grade, comorbidity index, facility type, geographic region, insurance status, and census-derived median income and education for the patient's zip code (OR 0.84, 95% CI: 0.77-0.93). pCR rate by race and molecular subtype RacepCR number (%)p valueER/PR+, Her 2-Non-Hispanic White943/5129 (18.4%)reference Non-Hispanic Black204/1042 (19.6%)0.367 Non-Hispanic Asian/Pacific Islander59/291 (20.3%)0.420 Hispanic121/609 (19.9%)0.373ER/PR+, Her 2 +Non-Hispanic White852/2107 (40.4%)Reference Non-Hispanic Black143/380 (37.6%)0.304 Non-Hispanic Asian/Pacific Islander42/124 (33.9%)0.148 Hispanic92/224 (41.1%)0.854ER/PR-, Her 2 +Non-Hispanic White698/1295 (53.9%)Reference Non-Hispanic Black116/272 (42.6%)0.001 Non-Hispanic Asian/Pacific Islander66/112 (58.9%)0.306 Hispanic88/174 (50.6%)0.409ER/PR-, Her 2-Non-Hispanic White1318/3079 (42.8%)Reference Non-Hispanic Black416/1138 (36.6%)&amp;lt;0.001 Non-Hispanic Asian/Pacific Islander64/165 (38.8%)0.310 Hispanic159/381 (41.7%)0.689 Conclusions Non-hispanic black women have a lower likelihood of pCR after neoadjuvant chemotherapy compared to white women for triple negative and Her 2 positive breast cancer. It is unknown whether this is due to biologic differences in chemosensitivity or whether it represents treatment or socioeconomic differences that cannot be adjusted for in the current analysis. Citation Format: Killelea BK, Chagpar AB, Horowitz NR, Pusztai L, Wang S, Mougalian S, Lannin DR. African American women have lower pathologic complete response rates to neoadjuvant chemotherapy compared to white women for triple negative and HER 2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-01.

Abstract P4-12-02: High HER2 gene amplification and clinical outcomes in localized HER2-positive breast cancer

Abstract BACKGROUND Anti-HER2 therapy with trastuzumab is associated with a significant improvement in disease-free survival as compared to chemotherapy alone, and is considered the standard of care for localized HER2 positive breast cancer. However, a subset of HER2 positive breast cancers do not respond to trastuzumab. While various mechanisms have been proposed for trastuzumab resistance, one potential contributor could be very high level of HER2 gene amplification. Since trastuzumab is a HER2 receptor antagonist, it is possible that single agent trastuzumab might be unable to block HER2 downstream signaling thresholds efficiently in the presence of very high HER2. The clinical outcomes for tumors with high HER2 gene amplification treated with trastuzumab have not been well studied. METHODS With IRB approval, we reviewed the clinical records of all Stage I-III breast cancer patients with HER2+ breast cancer at our institution from 2008-2012. HER-2 to Chromosome 17 FISH ratio was determined by two pathologists with high inter-person reliability using the PathVysion dual color probe (Abbott Laboratories). We abstracted data on demographics, tumor characteristics including tumor size (T), lymph node involvement, grade, DCIS, HER2 amplification levels, and clinical outcomes from the clinical charts. We defined high HER2 amplification as FISH ratio &amp;gt; 8.0, as used in the HERA trial. Categorical data are summarized by frequency and percentage and comparisons between groups are performed by chi-square tests. In addition, we conducted a meta-analyses and systematic review to evaluate the association between high HER2 gene amplification and clinical outcome with/without trastuzumab in the large adjuvant HER2 clinical trials. RESULTS A total of 503 patients with HER2+ breast cancer were seen between the years of 2008-2012, and 16% (N = 82) had tumors with high HER2 levels. The median age was 50.5 years (range 29-89). The majority of tumors were T1 (56.79%) or T2 (34.57%), and had HER2 IHC staining of 3+ (94.37%). Tumors with high HER2 levels were more likely to be ER-/PR- (48.4%) than ER+/PR+ (32.8%) or ER+/PR- (18.8%), and likely to have concomitant DCIS (82.5%) and high grade (grade 3 = 74%). Women (n = 16) with high HER2+ breast cancer treated with standard neoadjuvant therapy with single agent trastuzumab (AC-TH or TCH) had a low pathological complete response (pCR) rate of 7.14%. In addition, this group had a high recurrence risk of 42.9%. Two patients with recurrence had mutation profiling by multiplexed genotyping platform (SNaPshot) and mutations in PIK3CA and TP53 oncogene were identified.One patient with grade 3, high HER2+ (FISH 8.2) microinvasive DCIS, treated with mastectomy, developed pulmonary metastases 3 years after original diagnosis. The meta-analysis revealed adjuvant trastuzumab with chemotherapy did not result in improved disease free survival as compared to chemotherapy alone among tumors with high FISH ratio (Hazard Ratio: 0.89, 95% CI: 0.57, 1.38; p = 0.60). CONCLUSIONS: Our results suggest that tumors with high HER2 amplification, including small tumors, have an aggressive biology, are less likely to respond to standard trastuzumab based therapy, and more likely to have a recurrence, compared with historical HER2 controls. High FISH may predict a clone of cells that have resistance to single agent trastuzumab warranting more aggressive HER2 directed therapy such as dual HER2 or combined HER2 and PI3K/Akt/mTOR blockade. These findings need confirmation in additional studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-02.

Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer. Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0-8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection. In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection. This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.

Phase II trial of preoperative radiotherapy (RT) and panitumumab (PAN) in KRAS wild type (wt) rectal cancer (RC).

e14060 Background: The addition of anti Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mabs) to preoperative chemoradiation in RC has produced low pathological complete response (pCR) rate. The postulated reasons for the poor outcome are: lack of patient selection, suboptimal treatment sequencing, and potential negative interaction between anti EGFR mabs and chemotherapy (CT) when used concurrently as radiosensitizers. Given these issues, we conducted a phase II trial of PAN in combination with preoperative RT in Kras wt RC. Methods: We studied several treatment sequences in murine models of Kras wt human colorectal cancer. Next, we used our preclinical results to design the treatment schedule of the phase II trial. PAN (6mg/kg/q2w) was combined with RT (45 Gy) to treat T3-4, Kras wt RC. Surgery was done 6-8 weeks after the end of RT. The primary endpoint, the pCR rate on surgical specimen, was assessed centrally (Simon: H0=5%, H1=17%, α=0.05, β=0.2). Results: In our murine models, the addition of anti EGFR mabs to RT significantly improved response when anti EGFR mabs were started during RT and extended after the end of RT (p&lt;0.05). No benefit was found when anti EGFR mabs were given before the start of RT. In the phase II trial, we therefore started RT on day 1 and introduced PAN 7 days later (day 8). After RT ended (day 36), PAN treatment was continued to day 50. To fully explore PAN’s potential as radiosensitizer, CT was not given during RT but postoperatively. 19 patients were evaluable for pCR. 47% of tumours were cT3N+. Hypomagnesemia (16%) and hypophosphatemia (16%) were most common grade ≥3 toxicities. As no pCR was found, the study was closed prematurely for lack of efficacy according to the statistical rule. 7 patients (41%) had &gt;50% pathological tumour regression (grade 3 Dworak) and 12 (70%) showed &gt;2mm of tumour-free circumferential resection margin. Conclusions: Preclinical data confirm the need of optimal treatment sequencing to potentiate synergism between anti EGFR mabs and RT. However, the pCR rate in our phase II trial remains low despite adequate patient selection and optimized study design. Thus, we do not recommend the concurrent use of anti EGFR mabs and RT in the neoadjuvant treatment of RC.

Low pathologic complete response (pCR) rate to neoadjuvant chemotherapy in invasive lobular carcinoma of breast: Analysis of subgroup of four phase II trials

601 Background: Pathologic complete response (pCR) after preoperative chemotherapy (PCT) is associated with better outcome in locally advanced breast cancer (LABC). However, the pCR rate according to histology usually is not considered in trials. Methods: Patients (p) with histologically confirmed lobular carcinoma (LC), including in four phase II trials (AT, ATX, TXH, and BTX) conducted in our center, were eligible. Radiotherapy (RT) and hormone therapy (Ht) were allowed after surgery. Expression of markers was determined by IHC before CT. Primary objective of the study was to evaluate pCR rate in this subgroup of ps. Secondary endpoints were: clinical response rate (CRR), breast conservative surgery rate (BCSR), pathologic tumoral size (pTS), disease-free survival (DFS), and overall survival (OS). Results: A total of 185 ps including in the four trials were evaluated. Sixteen ps had LC (16/185 = 8.65%): median age = 50 y (38–66); premenopausal = 56.2%; left breast = 56.2%; median clinical (c) tumor size = 5 cm (3–6); stage:IIA = 6.7%; IIB = 26.7%; IIIA = 33.3%; IIIB = 33.3%; T:cT3 = 50%; cT4 = 28.6%; cN+ = 71.4% (median pN = 2 [0–32]); grade: G2 = 60%, G3 = 40%; ER+ = 78.6%; PgR+ = 64.3%; HER-2+ = 6.25%; phenotype by IHC: Luminal (HR+/HER-2-) = 75% (12/16); Luminal/HER-2+ (HR+/HER-2+) = 6.25%; triple negative (3/16) = 18.75%; p53+ = 25%; EGFR negative = 90%; median Ki-67 = 20% (5–70); adjuvant trastuzumab (H) = 6.25%; RT = 60%, median dose = 50Gy; Ht = 78.6% (tamoxifen = 55%; AI = 45%); type of PCT: docetaxel (T), capecitabine (X), and H (TXH) = 1p (6.2%); doxorubicin (A), T, and X (ATX) = 5 ps (31.2%); bevacizumab, T, and X (BTX) = 5 ps (31.2%); AT = 5 ps (31.2%); median of 5 cycles (2–6). Primary End-Point: Only 1 p (6.25%) had pCR in breast and nodes, and another p had a pCR only in breast, but not in nodes (pCR in breast = 2/16). Second End-Points: 1) CRR = 56.25% (complete = 12.5%; partial = 43.75%; no response = 37.5%; progression = 6.25%); 2) BCSR = 12.5%; 3) Median pTS = 2 cm(0 cm-6 cm); 4) Survival data are not mature. Only four events had occurred. With a median follow-up of 31 months, median DSF and OS has not been reached. Four-years DFS = 57%; and 3-y OS = 81%. Survival data will be updated in the meeting. Conclusions: PCT in LC is associated with very low pCR. No significant financial relationships to disclose.

Neoadjuvant Chemotherapy in Invasive Lobular Carcinoma May Not Improve Rates of Breast Conservation

Patients with invasive lobular carcinoma (ILC) experience a lower pathological complete response rate to neoadjuvant chemotherapy than patients with invasive ductal carcinoma. This study was intended to evaluate the impact of neoadjuvant chemotherapy in ILC on breast-conserving surgery (BCS) rates. Two-hundred eighty-four consecutive patients with pure ILC treated between May 1998 and September 2006 were reviewed. Surgical procedures and long-term outcomes were compared between patients receiving neoadjuvant chemotherapy and those receiving surgery first. Neoadjuvant chemotherapy was administered to 84 patients; 200 patients underwent surgery first. The mean tumor size in the neoadjuvant group (4.9 cm) was significantly larger than in patients who underwent surgery first (2.5 cm, p < 0.0001). In the neoadjuvant group, clinical complete response was seen in 10% and partial response in 59%. Overall BCS rates were 17% in the neoadjuvant group compared with 43% in the surgery-first group (p < 0.0001). When controlled for initial tumor size, there was no difference (all p > 0.05) between the groups in terms of (1) the proportion of patients who underwent an initial attempt at BCS, (2) rate of failure of BCS or (3) the proportion of patients undergoing BCS as their final procedure. With a mean follow-up of 47 months, local recurrence (LR) rates were similar between the two groups (1.2% versus 0.5%, p = 0.5). The use of neoadjuvant chemotherapy does not increase the rates of breast conservation in patients with pure ILC.

Phase I-II Trial of Cetuximab, Capecitabine, Oxaliplatin, and Radiotherapy as Preoperative Treatment in Rectal Cancer

To evaluate the safety and activity of preoperative radiotherapy (RT) with concurrent cetuximab, capecitabine, and oxaliplatin in rectal cancer patients. A total of 60 patients with rectal cancer (T3-T4 or N+, M1 allowed) entered the trial at five investigator sites; the data from 58 patients were assessable. Cetuximab was given as an initial dose of 400 mg/m2 7 days before the start of RT, and then at 250 mg/m2 once weekly during RT (50.4 Gy in 28 fractions). Capecitabine and oxaliplatin were administered according to an established schedule of oxaliplatin (50 mg/m2 on Days 1, 8, 22, and 29) and capecitabine (Days 1-14 and 22-35) at three dose levels: 1,000, 1,300, and 1,650 mg/m2/d during the Phase I part of the study. The main endpoint of the Phase II was the pathologic complete response rate. Thirteen patients were included in the Phase I part of the study, and the maximal tolerated dose was not reached. Overall, 48 patients were treated at the recommended dose of capecitabine (1,650 mg/m2) and 45 patients (94%) underwent surgery. A pathologic complete response was observed in 4 patients (9%), and moderate (n=12), minimal (n=10), and no tumor regression (n=2) was noted in 24 (53%) of 45 patients. The mean radiation dose intensity, cetuximab, capecitabine, oxaliplatin was 98%, 95%, 94%, and 94%, respectively. The incidence of Grade 3-4 diarrhea was restricted to 19%. Postoperative complications of any grade occurred in 33% of patients. The results of our study have shown that cetuximab can be combined safely with capecitabine and oxaliplatin plus RT. The low pathologic complete response rate achieved should stimulate additional preclinical investigations to establish the best sequence of triple combinations.