Lower 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.

AR Signaling in Breast Cancer.

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

Abstract P3-16-01: Immune characterization of inflammatory breast cancer and correlation to pathological complete response

Abstract Background: Treatment of inflammatory breast cancer (IBC) includes neoadjuvant chemotherapy (NAC) followed by mastectomy and radiation. Responses are limited however with low pathological complete response (pCR) rates and poor survival. Recent RNA expression studies suggest that activated T cell signaling pathways and immunomodulatory markers such as PD-L1 are associated with a higher pCR rate in IBC; however comprehensive studies of tumor infiltrating lymphocytes (TIL) and protein expression of immunomodulatory molecules are lacking. There is a critical need therefore to study molecular and immune determinants of therapeutic response in IBC, with the goal of identifying biomarkers and actionable strategies to improve treatment outcomes. Methods: Baseline core biopsies from 36 IBC patients, 22 with stage III and 14 with stage IV disease were evaluated. Of these, 21 stage III and 10 stage IV patients underwent mastectomy following NAC, the latter for palliative purposes. Tumor subtype distribution was 14 patients with HER2-/HR-, 6 with HER2+/HR-, 11 with HER2-/HR+, and 5 with HER2+/HR+ disease. TIL infiltration in the tumor stroma was quantified on H&E slides based on consensus guidelines as well as by immunohistochemistry (IHC) staining for CD8. PD-L1 expression in the TIL and invasive tumor was evaluated by IHC in tumors with >1%TIL. Results: Stromal TIL were found in the invasive tumor on pretreatment biopsies in 26 (72%) patients, with TIL percentages ranging from 1% to 60% (mean=11.6; sd=13.8); of note, 1 patient biopsy sample only had tumor emboli on the tissue block and therefore was not evaluable. Higher TIL infiltrate was noted in stage III versus stage IV disease (mean TIL 11.6% versus 3.5%, p=0.028). Mean TIL infiltrate was 11.5% in HER2-/HR-, 10.0% in HER2+/HR-, 10.4% in HER2+/HR+, and 3.6% in HER2-/HR+ tumors (p=NS). At mastectomy, 7/21 stage III patients and 1/10 stage IV patients achieved a pCR. Mean TIL was 13.4% in the pCR group versus 8.2% in the non-pCR group (p=0.37) CD8 and PD-L1 staining was performed on samples with >1%TIL (n=15, of which 14 samples were available for additional staining). An average of 42% of TIL stained positive for CD8 (range 10-80%). There was no significant relationship between %CD8 and pCR, stage, or receptor status. None of these 14 patients demonstrated membranous PD-L1 positivity but all had focal weak cytoplasmic staining in the lymphocytes. Conclusions: Differences exist in the presence of stromal TIL in distinct groups within IBC (stage III versus stage IV disease and across histologic subtypes) and may contribute to differential responses to therapy. When comparing these results to published non-IBC literature (FinHER trial), our IBC patient cohort had lower TIL infiltrate in several histologic subtypes (HER2-/HR- 11.5% vs 25%, p=0.015), HER2+/HR-(10% vs 20%, p=0.10), and HER-/HR+ disease (3.6 vs 7.5%, p=0.01); TIL was comparable for HER2+/HR+ disease. Additional studies are underway (including multiplex analysis of myeloid and lymphoid markers, T cell receptor sequencing, and molecular profiling) in pre-treatment and surgical samples to better understand mechanisms of treatment response and resistance. Citation Format: Reddy SM, Wargo JA, Reuben A, Reuben J, Woodward W, Ueno N, Mittendorf EA, Krishnamurthy S. Immune characterization of inflammatory breast cancer and correlation to pathological complete response [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-16-01.

New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer.

PI3K/AKT signaling pathway plays an important role in tumorigenesis and regulates critical cellular functions including survival, proliferation and metabolism. PIK3CA mutations and AKT activation by phosphorylation (pAKT) are often detected in many cancers and especially at high frequencies in breast cancer. Mounting data suggest that PIK3CA mutations or pAKT are mostly associated with better or insignificant outcomes in estrogen receptor-positive (ER+) early stage breast cancer and tend to be with worse prognosis in ER- disease. pAKT expression has been identified to predict paclitaxel chemotherapy benefit in node-positive breast cancer. Preclinical and neoadjuvant trial data suggest that PIK3CA alterations confer resistance to HER2-targeted therapy and are associated with lower pathological complete response (pCR) rate in HER2-positive breast cancer. However, recent results from randomized clinical trials of adjuvant and metastatic settings show that patients with mutant and wildtype PIK3CA tumors derived similar benefit from anti-HER2 therapy. This article, with our new insights, aims to decipher the mixed data and discusses the influence of the potential confounding factors in the assessments. We also share our views for validation of PI3K/AKT alterations in relation to clinical outcome in the context of specific breast cancer subtypes and treatment modalities towards further advance of the precision medicine for breast cancer treatment.

Abstract P3-07-03: PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study

Abstract Background: Phosphatidylinositol 3-kinase mutations (PIK3CA) are common in breast cancer (BC). Mutations are predominantly found in hot-spots located in the helical and kinase domains (exons 9 and 20). We recently demonstrated that PIK3CA mutations predict lower pathological complete response (pCR) to double blockade with trastuzumab/lapatinib in HER2+ve primary BC. Methods: We evaluated PIK3CA mutations in 293/403 HER2+ve tumors of participants of the neoadjuvant GeparSepto (G7) study (Untch et al. SABCS 2014). The G7 study investigated the effect of exchanging paclitaxel for nab-paclitaxel prior to EC. All patients received trastuzumab and pertuzumab. The G7 study showed a significantly higher pCR rate in patients receiving nab-paclitaxel. HER2, hormone receptors (HR), Ki67 and tumor infiltrating lymphocytes (TILs) were centrally assessed prior to randomization. PIK3CA mutations in exons 9 and 20 were evaluated in formalin-fixed, paraffin embedded core biopsies taken before therapy using deep targeted massive parallel sequencing with a minimum coverage of 500 and a mean coverage of 6520 and 6346 per amplicon, (exon9 and exon 20). Only non-synonymous mutations in the coding region that were called at variant allele frequency ≥10% were taken into consideration. Only cases with a tumor cell content of ≥20% were included. Results: In the G7 study, 396 patients with HER2+ve BC have been randomized from 06/2012 to 01/2014 and started treatment. From these 293 could be sequenced. Median age in the analyzed cohort was 49 years (range 22-75); most tumors were cT1-2 (89.9%); cN0 (54.4%); ductal invasive (88.7%), grade 3 (53.9%), HR+ve (69.6%), Ki67>20% (69.3%), LPBC-negative (83.2%). Overall, 22.2% of the tumors were found to have a PIK3CA mutation, 20.1% in HR+ve and 27.0% in HR-ve. Overall, the pCR rate was significantly lower in the PIK3CA mutant tumors compared to the wild type (wt) group (47.7% vs. 66.7%; p=0.009). This effect was seen both in the HR+ve (43.9% vs. 61.3%; p=0.052) and the HR-ve population (54.2% vs. 80.0%; p=0.029). There was also a significant difference in pCR according to PIK3CA mutation status dependant on the taxane. In the nab-paclitaxel group, pCR rates were significantly lower in patients with PIK3CA mutations compared to those without PIK3CA mutations (38.7% vs. 72.0%; p=0.001), whereas in the paclitaxel group, there was no significant difference between patients with and without a PIK3CA mutation (55.9% vs. 60.9%; p=0.690). The respective interaction could be demonstrated in univariate (p=0.039) as well as multivariate regression analysis (p=0.010) after adjusting for known baseline factors. Conclusion: Patients with PIK3CA mutant HER2+ve BC have a significantly lower pCR rate compared to patients with wt tumors. In contrast to the results with double anti-HER2 blockade consisting of trastuzumab/lapatinib, the effect was evident irrespective of the HR status. In addition, PIK3CA mutation status was significantly associated with higher pCR following nab-paclitaxel. The project has partly been funded within the EU-FP7 project RESPONSIFY No 278659 and the German Cancer Consortium (DKTK). Citation Format: Loibl S, Budczies J, Weichert W, Furlanetto J, Stenzinger A, Pfarr N, von Minckwitz G, Jackisch C, Schneeweiss A, Fasching P, Schmatloch S, Aktas B, Nekljudova V, Weber K, Untch M, Denkert C. PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study. [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 P3-07-03.

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%)<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 > 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<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 >50% pathological tumour regression (grade 3 Dworak) and 12 (70%) showed >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.

Using neoadjuvant therapy for breast cancer in clinical practice: when and how?

The roles of neoadjuvant therapy both as a standard thera-peutic approach and a research tool are very closely tied andhave yielded insights into both breast cancer biology andnew drug development [1, 2]. From a clinician’s standpoint,however, the key questions that arise revolve around theclinical advantages of neo-adjuvant therapy in terms ofsurgical outcomes, long-term recurrence/mortality anddecision-making. At the current time, the main advantage ofneoadjuvant therapy is to improve the odds of adequatesurgical resection, particularly breast-conserving surgery[3, 4]. Beyond that, long-term outcomes or clinical deci-sion-making do not appear to be affected by the sequence ofsystemic therapy in relation to definitive surgery. It isbecoming clear that breast cancer is heterogeneous. Ge-nomically defined subsets, which map to some extent withhormone and HER2 receptor subtypes, exhibit differentialrecurrence hazard reductions with systemic therapies—andthis concept also applies to neoadjuvant therapy response aswell [5]. But there is also clinical diversity, for example,contrasting rapid onset inflammatory cancer to a moreindolent cancer that has been clinically present for severalyears. Therefore, current neoadjuvant treatment paradigmsmust incorporate the base of evidence from large scaleclinical trials as well as the biological context of the disease.The reports contained in this special issue of Breast CancerResearch and Treatment highlight current trends and resultsthat are shaping both patient care and research in this area.The report by Lin et al.[6] demonstrate biological dif-ferences between interval and screen-detected cancerstreated on a prospective trial, even though the number ofscreening-detected cancers was small, as would be typicalin a neoadjuvant trial where the majority of patients werenot undergoing screening. As expected, interval cancershad a tendency to be hormone receptor-negative and ofhigher grade, whereas screen-detected cancers were all ofthe luminal intrinsic subtypes by gene expression array.Nevertheless, this report points to the need to stratifypatients by known characteristics associated with responsein clinical trials and to use established factors in routineclinical practice. For example, it is now clear that patientswith hormone receptor-positive cancer have less responseto neoadjuvant therapy and lower pathologic completeresponse (pCR) rates. Receptor status might thereforeaffect the decision regarding the timing of chemotherapy,especially if breast-conserving surgery is driving thedecision. Several phenotypes that are also related to hor-mone receptor content, but appear to have independentprognostic factors for response, such as proliferation indexand risk score by gene profile assays are the next markerson the horizon that could enter into this decision-making iftumor size reduction is a main goal of therapy [7, 8].Is there an optimum neoadjuvant regimen? Should non-standard adjuvant regimens that yield high pCR rates beadopted into routine practice? Until neoadjuvant trials arepowered for long-term outcome, at the current time, it isimportant to remember that the most important benefit ofneoadjuvant therapy is its ‘‘adjuvant’’ effect on long-termrecurrence and mortality. Therefore, an evidence-basedapproach would dictate the use of proven standard adjuvantregimens in the neoadjuvant setting. However, trials thatbridge pCR rates in relevant subsets to long-term outcomecould serve as the basis for approvals of new drugs andregimens and eventually shorten regulatory approval times[9]. Some long-standing standards may need to be

Pathologic response rates from neoadjuvant chemotherapy in muscle-invasive transitional cell carcinoma of the bladder.

e15181 Background: Neoadjuvant chemotherapy (NC) with MVAC for muscle invasive transitional cell carcinoma (TCC) of the bladder has been shown to improve survival, with pathologic complete response (pCR) serving as a robust predictor of survival benefit. While gemcitabine/cisplatin (GC) is often substituted in the neoadjuvant setting, positive randomized neoadjuvant data are available only for MVAC, and recent retrospective data have noted low pathologic complete response rates with GC. Methods: Data was retrospectively collected on 110 patients with T2-T4Nany TCC of the bladder who underwent radical cystectomy (RC) at the University of Washington Medical Center between September 2003 and July 2009. Information on clinical stage, neoadjuvant chemotherapy, comorbidities and pCR were collected. The prespecified primary endpoint was pCR rates comparing MVAC and GC neoadjuvant groups. Results: Of 110 patients, 43% received NC (total=47: GC=18, MVAC=12, dose dense MVAC=2, gem/carboplatin=7, other=8). Percentage of patients with advanced clinical stage at diagnosis as defined by T3 or greater or node positive was higher in patients administered NC and highest in those administered GC (any NC 43%, GC 72%, MVAC 50%, no NC 22%). pCR rates were significantly improved in patients undergoing NC versus surgery alone (28% vs. 12%, p=.03). No significant difference was noted in pCR rates (pT0) between GC and MVAC subgroups (33% vs. 17%, p=.31). When comparing rates of pCR allowing for residual in situ (pTIS) disease, NC provided superior response rates when compared with surgery alone (49% vs. 15%, p=.0001), and neoadjuvant GC provided superior response rates when compared to MVAC (67% vs. 25%, p=.025). Conclusions: Neoadjuvant chemotherapy for muscle invasive bladder TCC produced significantly increased pCR rates in comparison to surgery alone in patients who underwent RC at our institution. Interestingly, while there was no statistical difference in pathologic pT0 rates in the GC versus MVAC subgroups, when residual pTIS was allowed GC improved response rates over MVAC. These observations are in contrast to prior observations and support the use of GC as an alternative regimen in the neoadjuvant setting.

Antiepidermal growth factor receptor radiosensitizers in rectal cancer

The activation of the epidermal growth factor receptor (EGFR) pathway correlates with a worse prognosis in many solid tumours. Hence, EGFR inhibitors have been developed as a treatment for cancer. The EGFR inhibitor cetuximab has been successfully combined with radical radiotherapy in head and neck cancer. In metastatic colorectal cancer, cetuximab and panitumumab have activity as single agents, and increased response rates are achieved when added to standard chemotherapy schedules. This approach of using EGFR inhibitors has also been extrapolated to the preoperative treatment of locally advanced rectal cancer. Counterintuitively, the combination of chemotherapy, EGFR inhibitors and anti-VEGF antibodies seem to show lower response rates, suggesting antagonism. In rectal cancer, disappointingly low pathological complete response (pCR) rates have often been observed in chemoradiation regimens using EGFR inhibitors. In this study, we aimed to examine the rationale for the integration of EGFR inhibitors into chemoradiation schedules for rectal cancer. We have reviewed the clinical evidence and potential mechanisms for an interaction when EGFR inhibitors are added to fluoropyrimidine-based preoperative chemoradiation, the majority of which have used cetuximab. The primary outcome measure used was pCR. The overall pooled pCR for cetuximab-based chemoradiation was 10.71% (38/356). The rate of G3/G4 gastrointestinal toxicity, in terms of diarrhoea, varied from 5 to 30%, with an overall pooled rate of 13.8% (49/353). A better understanding of the mechanisms involved in combining chemotherapy and radiotherapy might allow more effective future scheduling of biological and chemical agents in combination with radiation.

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.

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.