Value Of Pathologic Complete Response Research Articles

Abstract PO1-16-04: Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression

Abstract Purpose: Low molecular weight isoforms of cyclin E (LMW-E) have been implicated in various human cancers, including triple negative breast cancer (TNBC), and are associated with a poor prognosis. However, targeted therapies for TNBC based on biomarkers are currently lacking. This study aims to investigate LMW-E as a potential therapeutic target in TNBC and evaluate the efficacy of RP-6306, a selective inhibitor of the Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1), in LMW-E-positive breast tumors. Experimental Design: Immunohistochemical (IHC) analysis was performed on pre-treatment tumor specimens from TNBC patients (n=36) to assess the correlation between LMW-E expression, CDK1 phosphorylation at Threonine 14 (pT14), and pathologic complete response to neoadjuvant chemotherapy. LMW-E inducible human mammary epithelial cells (hMEC) and breast cancer cell lines were used to investigate the regulatory effect of LMW-E on PKMYT1, the kinase responsible for CDK1 phosphorylation at T14, and the response to RP-6306, a first in-class and selective inhibitor of PKMYT1. Patient-derived xenograft (PDX) models and transgenic mouse mammary tumor virus (MMTV) models of TNBC expressing human LMW-E (hLMW-E) were also utilized to assess LMW-E as a biomarker for predicting response to RP-6306. Results. Analysis of TNBC tumor biopsies revealed a significant positive correlation between LMW-E expression and CDK1 pT14, and both biomarkers were associated with a lack of pathological complete response to neoadjuvant chemotherapy. In vitro results using LMW-E inducible hMECs and breast cancer cell lines demonstrated that LMW-E up-regulates PKMYT1 and CDK1 pT14, acting as a PKMYT1 binding protein and enhancing PKMYT1 protein stability. High LMW-E protein levels predicted a favorable response to RP-6306, resulting in the accumulation of sub-G1 and polyploid cells, decreased tolerance to replication stress, increased DNA damage, chromosomal breakage, and apoptosis. In vivo treatment of TNBC PDX models and hLMW-E transgenic tumors with RP-6306 resulted in a significant reduction in tumor volume only in mice harboring high LMW-E tumors, while low cyclin E models showed no response. Immunohistochemical analysis confirmed increased γ-H2AX and decreased CDK1-pT14 and Ki67 levels, indicating the efficacy of RP-6306 in both PDX and transgenic models. Conclusion: This study highlights the regulatory axis from LMW-E to PKMYT1 and its predictive value for pathological complete response in TNBC patients receiving neoadjuvant chemotherapy. The selective PKMYT1 kinase inhibitor RP-6306 consistently induced DNA damage and inhibited tumor growth in in vitro and in vivo pre-clinical breast tumor models. Co-expression of LMW-E and CDK1-pT14 in TNBC can be used to stratify patients whose tumors are likely to respond to RP-6306, emphasizing its therapeutic significance. Citation Format: Mi Li, Amriti Lulla, Cansu Karakas, Spiridon Tsavaschidis, Yan Wang, Tuyen Nguyun, Tuyen Bui, Gary Marshall, Kelly Hunt, Khandan Keyomarsi. Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-04.

Early-stage triple negative breast cancer: the therapeutic role of immunotherapy and the prognostic value of pathological complete response.

Triple negative breast cancer (TNBC) represents an aggressive disease associated with a high risk of recurrence after curative treatment and a poor prognosis in the metastatic setting. Chemotherapy was for years the only treatment available in the early and metastatic setting, due to the lack of actionable targets. Clinical practice has changed following the results obtained with the addition of immunotherapy to standard chemotherapy, the development of novel drugs [i.e. antibody-drug conjugates (ADCs)], and the use of targeted treatments for patients carrying germline pathogenic breast cancer susceptibility genes (BRCA) 1 or BRCA 2 variants. The treatment of early-stage disease has had a shift in clinical practice since July 2021, after the Food and Drug Administration (FDA) approval of pembrolizumab in association with chemotherapy as neoadjuvant treatment for TNBC and as a single agent in the subsequent adjuvant setting. This intensive treatment based on the combination of a poly-chemotherapy and an immune checkpoint inhibitor (ICI) led to the improvement of short- and long-term outcomes, but it has highlighted some new unmet clinical needs in the treatment of early-stage TNBC: the selection of the most effective adjuvant therapy and the integration of pembrolizumab with other therapeutic strategies [capecitabine, poly(ADP-ribose) polymerase (PARP) inhibitors] based on the achievement of pathologic complete response (pCR); the identification of predictive biomarkers to select patients who could most benefit from the addition of ICI, to minimize toxicities and to maximize outcomes; the possibility of de-escalating chemotherapy in favor of immune-combo or novel agents, such as ADCs; the role of immunotherapy in estrogen receptor (ER)-low patients. The advent of immunotherapy not only addresses current challenges in TNBC treatment but also holds the promise of a radical transformation in its therapeutic paradigm, enhancing significantly clinical outcomes and offering new perspectives for patients grappling with this aggressive form of breast cancer.

ASO Author Reflections: The Prognostic Value of Pathologic Complete Response After Neoadjuvant Chemotherapy in Gastric Cancer.

ASO Author Reflections: The Prognostic Value of Pathologic Complete Response After Neoadjuvant Chemotherapy in Gastric Cancer.

Novel peripheral blood parameters as predictors of neoadjuvant chemotherapy response in breast cancer.

The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune severity index (SII), and prognostic nutritional index (PNI) are associated with the prognosis of gastric, lung, and breast cancers. However, the predictive value of pathological complete response (pCR) rates in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) remains unclear. This retrospective study explored the correlation between each index and the efficacy of neoadjuvant chemotherapy in patients with breast cancer and assessed the relationship between changes before and after neoadjuvant chemotherapy. We enrolled 95 patients with locally advanced breast cancer who received neoadjuvant therapy for breast cancer at the Second Affiliated Hospital of Fujian Medical University from April 2020 to April 2022. Based on postoperative pathology, patients were divided into pCR and non-pCR groups. Between-group differences and efficacy prediction ability of NLR, PLR, SII, and PNI were analyzed. Patient characteristics and changes in NLR, PLR, SII, and PNI before and after neoadjuvant chemotherapy (NAC) were compared between groups. Patients were divided into two groups according to the optimal diagnostic thresholds of the SII before treatment. Between-group differences in terms of neoadjuvant therapy efficacy and patient characteristics were evaluated. The pCR exhibited significantly lower ER (χ 2 = 10.227, P = 0.001), PR (χ 2 = 3.568, P = 0.049), pretreatment NLR (χ 2 = 24.930, P < 0.001), pretreatment PLR (χ 2 = 22.208, P < 0.001), pretreatment SII (χ 2 = 26.329, P < 0.001), and post-treatment PNI (P = 0.032), but higher HER-2 (χ 2 = 7.282, P = 0.007) and ΔNLR (P = 0.015) than the non-pCR group. ROC curve analysis revealed that the areas under the curve (AUC) of pretreatment SII, NLR, and PLR for predicting pCR of NAC for breast cancer were 0.827, 0.827, and 0.810, respectively, indicating a higher predictive value for response to NAC in patients with breast cancer. According to the Youden index, the optimal cut-off value of SII pretreatment was 403.20. Significant differences in age (χ 2 = 6.539, P = 0.01), ER (χ 2 = 4.783, P = 0.029), and HER-2 (χ 2 = 4.712, P = 0.030) were observed between high and low-SII groups. In conclusion, pretreatment NLR, PLR, and SII can be used as predictors of pCR in patients with breast cancer receiving neoadjuvant chemotherapy. The predictive value of pretreatment SII is higher, and patients with low SII are more likely to achieve pCR.

Clinical Significance of Breast Cancer Molecular Subtypes and Ki67 Expression as a Predictive Value for Pathological Complete Response following Neoadjuvant Chemotherapy: Experience from a Tertiary Care Center in Lebanon.

Introduction Breast cancer is considered nowadays the most prevalent cancer worldwide. The molecular era has successfully divided breast cancer into subtypes based on the various hormonal receptors. These molecular subtypes play a major role in determining the neoadjuvant chemotherapy to be administered. It was noted that the use of neoadjuvant chemotherapy was associated with higher achievement of pathological complete response. The aim of the study was to determine the predictive role of breast cancer subtypes in the efficacy and prognosis of neoadjuvant chemotherapy regimens. Methods Combining dose dense anthracycline-based, regular dose anthracycline-based, and nonanthracycline-based chemotherapy, we observed data from 87 patients with breast cancer who received surgery after administration of neoadjuvant chemotherapy at our institution between January 2015 and July 2018. The patients were classified into luminal A, luminal B, HER2 overexpression, and triple negative breast cancer as well as low Ki67 (≤14%) and high Ki67 (>14%) expression groups using immunohistochemistry. Pathologic complete response was the only neoadjuvant chemotherapy outcome parameter. To evaluate variables associated with pathologic complete response, we used univariate analyses followed by multivariate logistic regression. Results 87 patients with breast cancer were classified into different subtypes according to the 12th St. Gallen International Breast Cancer Conference. The response rate to neoadjuvant chemotherapy was significantly different (p = 0.046) between the subgroups. There were significant correlations between pathological complete response (pCR) and ER status (p < 0.0001), HER2 (p = 0.013), molecular subtypes (p = 0.018), T stage (p = 0.024), N stage before chemotherapy (p = 0.04), and type of chemotherapy (p = 0.029). Luminal B type patients had the lowest pCR, followed by luminal A type patients. Conclusion Evaluating molecular subtype's significance in breast cancer prognosis warrants additional studies in our region with extensive data about patient-specific neoadjuvant chemotherapy regimens. Our study was able to reproduce results complementary to those present in the literature in other outcomes.

Pathological complete response after neoadjuvant treatment determines survival in esophageal squamous cell carcinoma patients (NEOCRTEC5010).

BackgroundFew studies have exclusively investigated the value of pathological complete response (pCR), in esophageal squamous cell carcinoma (ESCC) patients, although it is a clinically significant parameter to evaluate the impact of neoadjuvant chemoradiotherapy (nCRT) on treatment outcome after surgery. The aim of our study was to explore the relationship between pCR after nCRT and survival among patients with local ESCC.MethodsAll patients receiving nCRT followed by surgery in NEOCRTEC5010-trial (NCT01216527) were included. Non-pCR patients were classified into three subgroups: ypTanyN0M0, ypT0NanyM0 and ypTanyNanyM0. The Kaplan-Meier method with log-rank test was employed to evaluate disease-free survival (DFS) and overall survival (OS). Multivariate regression analysis was performed using a Cox proportional hazards model to identify clinicopathological parameters associated with pCR.ResultsAmong the 185 patients included, 80 (43.2%) achieved pCR after nCRT. The mean survival time of the pCR group was significantly longer than that of the non-pCR group (92.6 vs. 69.2 months; HR, 2.70; 95% CI: 1.48–4.92; P=0.001). The 5-year OS and DFS of the pCR group were 79.3% and 77% respectively, compared to 54.8% and 51.2%, respectively, in the non-pCR group. The results showed that the OS and DFS of the ypTanyN0M0 group were better than those of the ypT0NanyM0 group and the ypTanyNanyM0 group. We also found that the number of dissected lymph nodes and pCR were independent risk factors for DFS and OS rates.ConclusionspCR after nCRT is an important prognostic indicator of OS and DFS in patients with ESCC. In addition, lymph-node status could represent an important parameter in the prognostic evaluation of esophageal cancer patients.

Clinical outcomes of pancoast tumors treated with trimodality therapy.

BackgroundSuperior sulcus tumors, or Pancoast tumors, are challenging thoracic malignancies to treat due to their anatomical location posing difficult surgical access and potential involvement of adjacent vital structures. The current standard of care is trimodality treatment, which consists of induction chemoradiotherapy followed by radical surgical resection. This study aims to report the clinical outcomes of trimodality approach in British Columbia, Canada.MethodsPatients with Pancoast tumors who underwent trimodality treatment between 2000–2015 were included in this provincial multi-center retrospective study. Patient-, disease-, and treatment-related data were collected, and treatment outcomes were recorded.ResultsWe identified 32 patients who underwent induction chemoradiotherapy and subsequent surgical resection. Mean age was 59 (43–75 years) with median follow-up of 43 months (5–216 months). Complete resection was achieved in 31 patients (97%). Fourteen patients (44%) had pathological complete response after induction chemoradiotherapy. Thirteen (41%) showed minimal microscopic (>90% tumor necrosis) and 5 (16%) macroscopic residual disease (<90% tumor necrosis). Fourteen patients (44%) developed recurrence, which was distant in 9 cases. The 2-, 5-, and 10-year overall survival rates were 67.9%, 50.1%, 31.8% and the 2-, 5-, and 10-year disease-free survival rates were 65.1%, 47.1% and 28.2% respectively. There were no statistically significant differences in overall survival or disease-free survival rates with or without pathological complete response.ConclusionsComplete surgical resection with negative margins can be achieved after induction chemoradiotherapy, and curative-intent trimodality treatment can lead to long-term survival in some patients. This study did not demonstrate any prognostic value of pathological complete response, likely due to small sample size.

Integrating Adjuvant Radiation with Post-Neoadjuvant Therapies in Early Breast Cancer.

Because of the strong prognostic value of pathologic complete response (pCR) in early breast cancer (EBC), patients who fail to achieve this outcome have increasingly been eligible to a new treatment modality, namely post-neoadjuvant systemic therapy (PNT). However, adjuvant radiation therapy (RT) retains a crucial role in EBC, and also needs to be timely administered to patients. To address how modern PNT optimally integrates with adjuvant RT is therefore the purpose of this review. How PNT administration optimally integrates with adjuvant RT has varied depending on the type of systemic therapy employed. The introduction of novel "targeted" agents has created new challenges, as for many of them limited information is available on the feasibility of concurrent systemic and RT administration or their optimal sequencing. PNT and RT are both of utmost importance to the management of EBC and need to be timely and safely administered to patients. The optimal strategy to integrate these modalities may vary according to the type of PNT agent and other factors.

Clinical Outcomes of Pancoast Tumors Treated with Trimodality Therapy

Background Superior sulcus tumors, or Pancoast tumors, are challenging thoracic malignancies to treat due to their anatomical location posing difficult surgical access and potential involvement of adjacent vital structures. The current standard of care is trimodality treatment, which consists of induction chemoradiotherapy followed by radical surgical resection. This study aims to report the clinical outcomes of trimodality approach in British Columbia, Canada. Methods Patients with Pancoast tumors who underwent trimodality treatment between 2000-2015 were included in this provincial multi-center retrospective study. Patient-, disease-, and treatment-related data were collected, and treatment outcomes were recorded. Results We identified 32 patients who underwent induction chemoradiotherapy and subsequent surgical resection. Mean age was 59 (43-75 years) with median follow-up of 43 months (5-216 months). Complete resection was achieved in 31 patients (97%). Fourteen patients (44%) had pathological complete response after induction chemoradiotherapy. Thirteen (41%) showed minimal microscopic (>90% tumor necrosis) and 5 (16%) macroscopic residual disease (<90% tumor necrosis). Fourteen patients (44%) developed recurrence, which was distant in 9 cases. The 2-, 5-, and 10-year overall survival rates were 67.9%, 50.1%, 31.8% and the 2-, 5-, and 10-year disease-free survival rates were 65.1%, 47.1% and 28.2% respectively. There were no statistically significant differences in overall survival or disease-free survival rates with or without pathological complete response. Conclusions Complete surgical resection with negative margins can be achieved after induction chemoradiotherapy, and curative-intent trimodality treatment can lead to long-term survival in some patients. This study did not demonstrate any prognostic value of pathological complete response, likely due to small sample size.

Prognostic significance of pathological complete response in non-small cell lung cancer following neoadjuvant treatment.

This study aims to investigate the factors associated with pathological complete response following neoadjuvant treatment and to examine the prognostic value of pathological complete response in patients with non-small cell lung cancer undergoing surgical resection. Between February 2009 and January 2016, a total of 112 patients (96 males, 16 females; mean age 60±8 years; range, 37 to 85 years) with the diagnosis of non-small cell lung cancer who underwent anatomical pulmonary resection after neoadjuvant treatment were retrospectively analyzed. Demographic, clinical, radiological, and pathological characteristics of the patients were recorded. The patients were classified as pathological complete response and nonpathological complete response according to the presence of tumors in the pathology reports. Predictive factors for pathological complete response and its prognostic significance were analyzed. The mean follow-up was 35±20 (range, 0 to 110) months. Of the patients, 30 (27%) achieved a pathological complete response. Reduction rate in tumor size was significantly higher in the responsive group (32.5±21.6% vs. 19.2±18.8%, respectively) and was a predictor of pathological complete response independent from the T and N factors (p=0.004). Survival of the responsive patients was significantly longer than unresponsive patients (75±9 vs. 30±4 months, respectively; p<0.001). During follow-up, tumor recurrence was seen in 30 patients. Recurrence was observed in only one patient in the responsive group, while 29 patients in the unresponsive group had recurrence or metastasis. Tumor shrinkage rate after neoadjuvant treatment in non-small cell lung cancer is a predictive factor for pathological complete response. Survival of patients with a pathological complete response is also significantly longer than unresponsive patients.

Predictive factors and prognostic value of pathologic complete response of ipsilateral supraclavicular lymph nodes in breast cancer after neoadjuvant chemotherapy

Breast cancer with ipsilateral supraclavicular lymph node metastasis is one of the indicators of poor prognosis. Patients who attain pathologic complete response in breast and axillary sites have improved survival and are highest in aggressive HR-HER2- and HER2-positive tumor subtypes. However, there is no study on the related factors and prognostic value of supraclavicular pathologic complete response in breast cancer after neoadjuvant chemotherapy. The aim of our work was to investigate the factors and prognostic significance of pathologic complete response of ipsilateral supraclavicular lymph node metastasis in breast cancer after neoadjuvant chemotherapy. A total of 214 patients with breast cancer who had primary ISLN metastasis, receiving NAC and subsequent ISLN dissection, were retrospectively and consecutively reviewed. Univariate and multivariate analyses were performed using χ2 test and the logistic regression model, and the prognosis was analyzed by Kaplan-Meier curve. All patients included were women who were 26-74 years old. The rate of supraclavicular pathologic complete response (pCR) was 53.7%. Multivariate analysis showed that the expression of Ki67, breast pCR, and axillary pCR were independent predictors of supraclavicular pCR (P<0.05). After a median follow-up of 16.2 months, the risk of recurrence and metastasis in patients with supraclavicular pCR was half reduced compared to that of the non-pCR group (HR 0.51, 95% CI, 0.32-0.80, P<0.01), mainly manifested in HR-HER2- and HER2-positive disease. The expression level of Ki67, breast pCR, and axillary pCR were independent predictors of supraclavicular pCR. Supraclavicular pCR was an independent predictor of disease-free survival (DFS). Surgical removal of supraclavicular lymph nodes can accurately evaluate the rate of supraclavicular pCR, which is of great significance for patient prognosis.

Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel.

Prognostic value of pathologic complete response (pCR) and extent of pathologic response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC. One-hundred and ninety patients with stage I-III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m2) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan-Meier method. Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14-0.62; P = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10-0.63; P = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS. Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.

From PCR to miRNA profiling: Where is the true?

e12665Background: The prognostic value of pathological complete response (pCR) on survival is still debated. Previous studies have revealed that breast cancer intrinsic subtypes show different mole...

The Prognostic Effect of Changes in Tumor Stage and Nodal Status After Neoadjuvant Chemotherapy in Each Primary Breast Cancer Subtype

BackgroundAlthough the prognostic value of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depends on the intrinsic subtype of breast cancer, it is not clear whether chemosensitivity itself, shown by a decreasing tumor burden after NAC, contributes to improved prognosis in primary breast cancer patients, especially in patients with non-pCR. The aim of this study was to assess the prognostic effect of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype. Patients and MethodsWe assessed 719 consecutive patients with primary breast cancer who underwent surgical resection after NAC between 2001 and 2010. The patients were divided into 5 subtypes according to their hormone receptor (HR) status, HER2 status, and nuclear grade (NG; 1/2 = low, and 3 = high). ResultsIn patients with HR-positive (HR+)/HER2−/NG-low tumors, regardless of change in tumor size, the loss of node positivity after NAC significantly improved disease-free survival (DFS). In patients with HR+/HER2−/NG-high tumors, achievement of tumor downstaging as well as the loss of node positivity improved their DFS. In patients with HR−/HER2− tumors, tumor downstaging and the loss of node positivity significantly improved DFS, despite a non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved. ConclusionOur results revealed that changes in tumor stage and nodal status after NAC might be prognostic markers in patients with HR+/HER2−/NG-high tumors or HR−/HER2− tumors, even if there are residual tumors in the breast.

Outcome after neoadjuvant chemotherapy in Asian breast cancer patients.

We aim to identify clinicopathologic predictors for response to neoadjuvant chemotherapy and to evaluate the prognostic value of pathologic complete response (pCR) on survival in Asia. This study included 915 breast cancer patients who underwent neoadjuvant chemotherapy at five public hospitals in Singapore and Malaysia. pCR following neoadjuvant chemotherapy was defined as 1) no residual invasive tumor cells in the breast (ypT0/is) and 2) no residual invasive tumor cells in the breast and axillary lymph nodes (ypT0/is ypN0). Association between pCR and clinicopathologic characteristics and treatment were evaluated using chi‐square test and multivariable logistic regression. Kaplan–Meier analysis and log‐rank test, stratified by other prognostic factors, were conducted to compare overall survival between patients who achieved pCR and patients who did not. Overall, 4.4% of nonmetastatic patients received neoadjuvant chemotherapy. The median age of preoperatively treated patients was 50 years. pCR rates were 18.1% (pCR ypT0/is) and 14.4% (pCR ypT0/is ypN0), respectively. pCR rate was the highest among women who had higher grade, smaller size, estrogen receptor negative, human epidermal growth factor receptor 2‐positive disease or receiving taxane‐based neoadjuvant chemotherapy. Patients who achieved pCR had better overall survival than those who did not. In subgroup analysis, the survival advantage was only significant among women with estrogen receptor‐negative tumors. Patients with poor prognostic profile are more likely to achieve pCR and particularly when receiving taxane‐containing chemotherapy. pCR is a significant prognostic factor for overall survival especially in estrogen receptor‐negative breast cancers.

EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer

The EndoPredict (EP) signature is a prognostic 11-gene expression signature specifically developed in ER+/HER2– node-negative/positive breast cancer. It is associated with relapse-free survival in patients treated with adjuvant hormone therapy, suggesting that EP low-risk patients could be treated with adjuvant hormone therapy alone whereas high-risk patients would deserve addition of adjuvant chemotherapy. Thus, it is important to determine whether EP high-risk patients are or are not more sensitive to chemotherapy than low-risk patients. Here, we have assessed the EP predictive value for pathological complete response to neoadjuvant chemotherapy in ER+/HER2– breast cancer. We gathered gene expression and histoclinical data of 553 pre-treatment ER+/HER2– breast carcinomas treated with anthracycline-based neoadjuvant chemotherapy. We searched for correlation between the pathological complete response (pCR) and the EP score-based classification. The overall pCR rate was 12%. Fifty-one percent of samples were classified as low-risk according to the EP score and 49% as high-risk. EP classification was associated with a pCR rate of 7% in the low-risk group and 17% in the high-risk group (p < 0.001). In multivariate analysis, the EP score remained significantly associated with pCR. Many genes upregulated in the high-risk tumours were involved in cell proliferation, whereas many genes upregulated in the low-risk tumours were involved in ER-signalling and stroma. Despite higher chemosensitivity, the high-risk group was associated with worse disease-free survival. In conclusion, EP high-risk ER+/HER2– breast cancers are more likely to respond to anthracycline-based chemotherapy.

Clock genes expression in breast cancers (BC) from patients (pts) treated with neoadjuvant chemotherapy (NAC) in a randomized multicenter phase II trial.

e11528 Background: Circadian clocks control cellular metabolism and proliferation. Circadian disruption could affect BC development and treatment efficacy. Purpose: To determine the relevance of 17 core clock genes as prognostic factors and their predictive value for pathological complete response (pCR) to NAC and disease-free survival. Methods: Tumor biopsies from 189 BC pts in a randomized Phase II trial were available for DNA microarrays (Pierga, BCRT, 2010; De Cremoux, Breast 2013). Transcriptome was determined with Affymetrix chip. Three metagenes were identified using Non negative Matrix Factorization. Genes recapitulating a metagene were defined by r > 0.7 (Pearson). Principal component analysis (PCA) discriminated groups according to clock genes expression. Differential analysis using LIMMA’s package scrutinized clock genes according to BC characteristics, pCR and DFS. Results: No clock gene expression was correlated to the metagenes. PCA did not discriminate any group according to individual cloc...

Abstract P1-08-09: EGFR expression is associated with decreased response from HER2 targeted therapeutics in the neo-adjuvant setting in the NeoALTTO trial

Abstract Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may modulate the effectiveness of trastuzumab or lapatinib. Historically, it has been difficult to measure, but recently we reported a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody which showed that high levels of EGFR were associated with decreased benefit in the concurrent arm of the North Central Cancer Treatment Group (NCCTG/Alliance) N9831 trial (Rimm et al, SABCS 2012). Here we assess its value in the neo-adjuvant setting in the NeoALTTO trial. Methods: NeoALTTO randomized 455 breast cancer patients to neoadjuvant trastuzumab, lapatinib or both and showed benefit in both single anti-HER2 therapy arms, and the combination therapy showing about twice as much benefit as either single drug arm. We used the previously described AQUA method of quantitative immunofluorescence to measure EGFR levels using the D38B1 antibody on between 4 and 140 fields of view per slide on 353 specimens. The averaged EGFR score was standardized to the absolute concentration using cell lines and western blots and the 13 ng/ug total protein established in the N9831 trial was tested to determine predictive value for pathological complete response (pCR) defined as ypT0/is. Results: In NeoALTTO, 19% of the patients had EGFR levels above 13 ng/ug, compared to 16% in NCCTG N9831. The pCR rate was 35.3% in the patients with low EGFR, compared with 29.8% for high EGFR but this difference was not statistically significant. However, when adjusted for treatment and hormone receptor (HR) status, high EGFR is statistically significantly associated with lower response rate(p = 0.038). Continuous analysis measures were not significant. The effect on overall response at 6 weeks was also weakly significant when adjusting for treatment and HR status (p = 0.06). Surprisingly, for HR negative patients in the lapatinib only arm, the pCR rate in the low EGFR group was 47.2% compared with 16.0% in the high group. While this difference is statistically significant (p = 0.014), it should be interpreted cautiously because of the small numbers of patients and the multiple tests performed. Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased pCR rate from HER2 targeted therapy in the neoadjuvant setting. This observation is consistent with NCCTG N9831. Although underpowered, high EGFR levels predicted decreased pCR rate from lapatinib, the opposite of that anticipated for this small molecule dual EGFR/HER2 inhibitor. Further studies are required to determine the clinical utility of this assay and the biological mechanisms underlying these observations. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-09.

Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer

Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is currently unknown. A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression. We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test p = 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (p = 0.003), young age (p = 0.037), and high tumor grade (p = 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test p = 0.040). No significant difference in survival was detected according to SphK1 expression. Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.

Update on neoadjuvant/preoperative therapy of breast cancer

Neoadjuvant treatment is used by an increased number of patients with breast cancer. This study reviews the current literature on how new research findings have impacted patients and treatment selection. The prognostic value of pathological complete response (pCR) is different in various breast cancer subtypes. pCR rate after neoadjuvant chemotherapy is associated with better outcome only for patients with human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor negative or HER2-negative/hormone receptor negative (triple-negative) and some more aggressive HER2-negative/hormone receptor positive tumours. Knowledge on pCR in these subtypes can relieve patients from an initially unfavourable prognosis. For patients without a pCR, especially if a high proliferation can be detected in the residual tumour after neoadjuvant treatment, prognosis is still unfavourable and clinical trials exploring new targeted agents in this postneoadjuvant indication are currently under development. Neoadjuvant treatment allows treatment to be guided by monitoring response. Changing the regimen in case of no early response or intensification in case of early response has shown significant survival advantages especially in patients with hormone receptor positive tumours. The model of neoadjuvant chemotherapy has been improved over the last decade and is now successfully used to increase our knowledge not only on the pathophysiology of the disease but also on the activity of conventional and new treatment approaches.