Residual Tumor Cellularity Research Articles

A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer

BackgroundNeoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI).MethodsIn this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size.ResultsOur results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0–80); radiological-TS by USS 9 (0–31); by MRI: 12 (0–60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value.ConclusionOur findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

Residual Tumor Cellularity Assessment of Breast Cancer After Neoadjuvant Therapy Using Image Transformer

Residual Tumor Cellularity Assessment of Breast Cancer After Neoadjuvant Therapy Using Image Transformer

Pathological response in mucinous carcinoma of breast after neoadjuvant therapy - a multi-institutional study

Although mucinous carcinoma (MC) is considered a favorable histologic subtype of invasive breast cancer (BC), a subset of MC is managed with neoadjuvant therapy (NAT). The clinical and pathologic features of MC following NAT are not well characterized. The aim of this study is to characterize pathologic response in patients with MC treated with NAT, including neoadjuvant endocrine therapy (NET), neoadjuvant chemotherapy (NCT), and Herceptin-targeted NCT (H-NCT). We conducted a retrospective cohort study of 28 patients with MC who received preoperative adjuvant therapy followed by resection from three institutions between 2010 and 2020. Demographic and clinical information were retrieved from the medical records. Pathologic review of the post NAT resection specimens was performed including tumor grading, tumor size, staging, residual tumor cellularity, estrogen receptor (ER) and HER2 status. Nine (32 %) patients with ER+/HER2- MC received NET, 8 (29 %) ER+/HER2- MC were treated with NCT only and 11 (39 %) HER2+ MC received HER2-targeted NCT (H-NCT). The HER2+ MC patients were younger (45 vs. 64 years; p = 0.006). The HER2+ MC were of higher grade (p = 0.03) and more likely to be multifocal (p = 0.008). Only 2 of 28 (7 %) MC (both HER2+) showed complete pathologic response with residual acellular mucin pools. Persistent mass-forming mucin pools were present in 26 (93 %) cases. The residual tumor cellularity was markedly reduced (≤5 %) in H-NCT treated MC (11/11, 100 %), followed by NET group (6/9, 67 %) and NCT only group (4/8, 50 %) (p = 0.011). Similarly, a higher rate of pathologic response (pCR/RCB-I) was observed in H-NCT (7/11, 64 %), followed by NET group (5/9, 56 %), and NCT only group (1/7, 13 %) (p = 0.053). Post-therapy, all HER2+ MC were smaller than 2 cm and ypT size was significantly smaller in H-NCT group (11/11, 100 %) versus combined NET (5/9, 55 %) and NCT only groups (4/8, 50 %) (p = 0.029). We conclude that ER-/HER2+ and ER+/HER2-mucinous carcinomas of the breast show robust pathological response to neoadjuvant HER2 targeted and endocrine therapy, respectively. Our findings suggest that MC may show good response to endocrine therapy.

Biomarker dynamics affecting neoadjuvant therapy response and outcome of HER2-positive breast cancer subtype

HER2+ breast cancer (BC) is an aggressive subtype genetically and biologically heterogeneous. We evaluate the predictive and prognostic role of HER2 protein/gene expression levels combined with clinico-pathologic features in 154 HER2+ BCs patients who received trastuzumab-based neoadjuvant chemotherapy (NACT). The tumoral pathological complete response (pCR) rate was 40.9%. High tumoral pCR show a scarce mortality rate vs subjects with a lower response. 93.7% of ypT0 were HER2 IHC3+ BC, 6.3% were HER2 IHC 2+/SISH+ and 86.7% of ypN0 were HER2 IHC3+, the remaining were HER2 IHC2+/SISH+. Better pCR rate correlate with a high percentage of infiltrating immune cells and right-sided tumors, that reduce distant metastasis and improve survival, but no incidence difference. HER2 IHC score and laterality emerge as strong predictors of tumoral pCR after NACT from machine learning analysis. HER2 IHC3+ and G3 are poor prognostic factors for HER2+ BC patients, and could be considered in the application of neoadjuvant therapy. Increasing TILs concentrations, lower lymph node ratio and lower residual tumor cellularity are associated with a better outcome. The immune microenvironment and scarce lymph node involvement have crucial role in clinical outcomes. The combination of all predictors might offer new options for NACT effectiveness prediction and stratification of HER2+ BC during clinical decision-making.

Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients.

Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns. Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method. Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC <40%; no difference was observed in terms of OS between RTC <40% and RTC ≥40% groups. Tumor stage before NAC, BC sub-type, and vascular invasion are significant and independent factors associated with pCR. Patients with pCR and with RTC <40% have longer DFS, DDFS, and OS compared with patients with pPR.

Abstract P6-01-15: Breast cancer patients with different hormone receptor subtypes receiving neoadjuvant chemotherapy (NAC) experience differential overall survival according to their resistance to NAC

Abstract Background: Response to neoadjuvant chemotherapy (NAC) is an indicator of outcomes and can be quantified as achievement of pathologic complete response (pCR) (absence of residual invasive disease in breast and lymph nodes) and residual percent cellularity. However, the significance of residual tumor cellularity post-NAC is not well understood. We assessed the impact of NAC-induced reduction in tumor cellularity among hormone receptor subtypes and the effect of these reductions on overall survival (OS). Methods: An IRB-approved retrospective review identified demographics, disease presentation, response to treatment, and outcomes. ER and PR status were categorized as low positive (1-9%), positive (≥ 10%) and negative. Treatment response was noted as percent residual cellularity (complete 0%, almost complete &amp;lt; 10%, good 10-30%, moderate &amp;gt;30-80% and poor &amp;gt;80%) in the surgical specimen and pathologic stage. We examined measures of response to NAC within breast tumor subtypes and the effect of these responses on associations with OS among hormone receptor subtypes. Results: The clinical series comprised 384 patients who received curative intent NAC. This series was diverse in presentation, displayed considerable variability in response to NAC (Table 1). 88 (23.6%) patients did not experience tumor down staging, and of those presenting with clinical nodal Stage 1 or higher (n=197), 94 (47.7%) did not experience nodal down staging. Although Triple Negative Breast Cancer (TNBC) status was not significantly associated with post-NAC residual tumor cellularity (p=0.74), ER, PR, and HER2 status were individually associated with this measure of response to NAC (p=0.04, 0.01, and 0.01, respectively). However, none of these associations explained more than 2.5% of the variability in this marker of treatment response. Median non-censored follow-up time was 4.26 years. Accounting for censoring, median survival was 13.65 years (lower 95% confidence limit was 11.79 years). Differential associations with OS were observed for three hormone receptor subtypes (ER: p&amp;lt; 0.001, HER2: p=0.04, and TNBC: p&amp;lt; 0.001) according to residual tumor cellularity, classified by percent residual cellularity categories of complete or almost complete response versus all others. Importantly, although ER negative patients with poor residual cellularity response had worse OS than ER positive patients with good response (Hazard Ratio [HR], 95% Confidence Interval [CI] = 4.74, 2.2-10.2), ER negative patients with good response did not have significantly worse OS than ER positive patients with good response (HR, 95% CI = 1.37, 0.57-3.26). Similar patterns were seen for patients with HER2 negative breast cancer or TNBC. Chemo resistant TNBC patients had higher risks for mortality than if they were not chemo resistant (HR, 95% CI: 2.41, 1.02-5.71). Conclusions: Our data suggest that OS associated with different hormone subtypes differs according to response to NAC. Differential OS according to response to NAC is greatest for patients classified according to ER status influences, with good response eliminating much of the differential mortality risk between ER negative and positive patients. There is a similar difference according to TNBC, although the difference appears to be less complete. Further studies should focus on understanding the chemo resistance of ER negative tumors, and perhaps TNBC, to identify mechanisms that may ultimately drive treatment response and survival. Table 1. Demographic and other characteristics Citation Format: Sangeetha Prabhakaran, V. Shane Pankratz, Christopher McNicoll, Nadja Falk, Jacklyn Nemunaitis, Jain Zhou, Payton Sandoval-Belt. Breast cancer patients with different hormone receptor subtypes receiving neoadjuvant chemotherapy (NAC) experience differential overall survival according to their resistance to NAC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-15.

Abstract P6-01-32: Evaluation of pathologic response and residual tumor cellularity following neo-adjuvant chemotherapy predict prognosis in breast cancer patients

Abstract Introduction: Treatment of early-stage beast cancer (BC) has changed since recent evidence showed that neoadjuvant chemotherapy (NAC) can reduce residual tumor cellularity (RTC) and improve patient outcomes. Achieving a pathologic complete response (pCR) has been associated with significantly improved disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). However, among patients treated with NAC, few experience pCR, while approximately 60-80% of them achieve a pathologic partial response (pPR). In previous studies, BC patients with different grades of pPR have been usually grouped and analyzed together, with inconsistent results and unclear prognostic significance. Objectives: The primary aims of this study were to describe the clinical and treatment characteristics of BC patients treated with NAC, to identify independent predictive factors of pCR, and to compare the oncologic outcomes between patients achieving pCR or pPR. The secondary aim of this study was to measure the RTC of BC patients with pPR and to compare the outcomes of patients with different RTC in order to improve prognostic information. Methods: All the consecutive BC patients undergoing NAC at the Breast Unit of IRCCS Humanitas Research Hospital (Milan, Italy) between October 2006 and April 2020 and their corresponding post-operative pathology slides were reviewed. The following exclusion criteria were used: excisional biopsy or debulking surgery as first BC operation, patients with a previous BC diagnosis or other prior or synchronous malignancies, male patients, unknown NAC regimen, disease progression during NAC, and follow-up ≤12 months. Results: A total of 495 BC patients received NAC. Overall, 148 (29.9%) patients achieved pCR, while 347 (70.1%) had pPR, and median RTC was 40%. At multivariable analysis, 3 independent factors predicting pCR were identified. Tumor stage pre-NAC (cT1-2 84.5% versus cT3-4 15.5%, odds ratio (OR)=0.119, 95% confidence interval (95%CI)=0.048-0.189, p=0.001), BC sub-type (HER2-enriched 54.7% versus triple-negative 29.8% versus luminal-like 15.5%, OR=2.178, 95%CI=2.055-2.301, p=0.001), and vascular invasion (absence 98.0% versus presence 2.0%, OR=0.022, 95%CI=0.004-0.090, p=0.001). Patients with BC undergoing NAC and achieving pCR presented statistically significant longer DFS, DDFS, and OS (p = &amp;lt; 0.001). Patients with RTC &amp;lt; 40% presented statistically significant better DFS and DDFS (p = 0.033, p = 0.015, respectively). However, no statistically significant difference in terms of OS was observed between RTC &amp;lt; 40% and RTC ≥40% groups (p = 0.148). Conclusions: Tumor stage pre-NAC, BC sub-type, and vascular invasion are significantly and independently associated with pCR. Patients with pCR present a better prognosis compared to patients with pPR in terms of DFS, DDFS, and OS. Measurement of RTC in BC patients with pPR improves the prognostic information that can be obtained from the assessment of the pathologic response. Different patterns of residual disease play an important role in predicting the risk of subsequent loco-regional and distant recurrence, and patients with RTC &amp;lt; 40% present significantly better DFS and DDFS. Citation Format: Damiano Gentile, Andrea Sagona, Camilla De Carlo, Bethania Fernandes, Simone Di Maria Grimaldi, Erika Barbieri, Wolfgang Gatzemeier, Lorenzo Scardina, Ersilia Biondi, Flavia Jacobs, Giulia Vatteroni, Corrado Tinterri. Evaluation of pathologic response and residual tumor cellularity following neo-adjuvant chemotherapy predict prognosis in breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-32.

Phase 2 Study of Preoperative SABR for Early-Stage Breast Cancer: Introduction of a Novel Form of Accelerated Partial Breast Radiation Therapy

Pre-operative delivery of partial breast irradiation (PBI) facilitates smaller target volumes and reduced dose to normal tissues. We hypothesized that pre-operative stereotactic ablative radiotherapy (SABR) delivered to intact breast tumor would achieve pathological complete response (pCR) in 25% of patients while preserving low rates of toxicity and good cosmesis. Eligible patients had hormone receptor-positive, clinically node-negative breast cancer measuring ≤2cm on magnetic resonance imaging (MRI). Patients received SABR to 28.5 Gy in three fractions of 9.5 Gy to the tumor defined on MRI and computed tomography in the prone position. Lumpectomy was performed 6-8 weeks later. Tumor pathologic response was assessed and adverse events (AEs) were rated on the Common Terminology Criteria for AEs version 4.0 scale. Physician-rated cosmesis are also reported. Twenty patients were enrolled and completed treatment; the study was terminated prior to full accrual due to pre-specified stopping rules. Median follow-up was 14 months. Median patient age was 65 years (range 54-78) and median tumor size on MRI was 10.5mm (range 5-22). All patients had negative surgical margins. Four patients (20%) required post-operative whole breast and axillary radiation due to positive sentinel lymph nodes. No pCR were observed, although the median percent residual tumor cellularity was 30% (range 10-80) and 90% had ≤50% residual cellularity. Three patients had late grade 3 AEs, including 2 of the 4 patients who received post-operative RT. Cosmesis was good in 85% of cases, fair in 10%, and poor in 5%. We observed a 0% incidence of pCR with pre-operative SABR for early-stage BrCa as evaluated 6-8 weeks following treatment. Evolution of pCR may require longer than 6-8 weeks. Patients requiring post-operative whole breast radiotherapy after pre-operative SABR may be at increased risk for high-grade soft tissue toxicity. Further studies are needed to determine optimal patient selection, treatment methodology and timing of pathologic response evaluation.

Abstract 3686: Differences in disease presentation, and treatment outcomes of neoadjuvant chemotherapy for breast cancer among Hispanics in a minority-serving institution

Abstract Background: Response to neoadjuvant chemotherapy (NAC) for breast cancer varies by tumor characteristics and therapy regimen. Studies suggest that patient ethnicity is associated with differences in disease presentation, response to treatment, and outcomes. There exists a paucity of literature on the presentation and outcomes of NAC for breast cancer in Hispanic women. Methods: This is an IRB-approved retrospective study of breast cancer patients who underwent NAC at an NCI-designated Comprehensive Cancer Center from 2005-2020. We reviewed demographics, disease presentation, response to treatment, and outcomes. ER and PR status were categorized as low positive (1-9%), positive (≥ 10%) and negative. Treatment factors reviewed included completion of chemotherapy and type of surgery performed. Treatment response was noted as percent residual cellularity (0%, &amp;lt;10%, 10-30%, &amp;gt;30-80% and &amp;gt;80%) in the surgical specimen and pathologic stage. Outcomes were assessed as overall survival (OS) and recurrence. Results: 365 patients received neoadjuvant chemotherapy from 2005-2020, and 196 (53.7%) self-identified as Hispanic. Median follow-up was 13.65 years. Highest clinical stage at diagnosis was most frequently IIA (31.2%), followed by IIB (32.3%), with non-significant Hispanic ethnicity differences, although Hispanic patients presented with higher clinical prognostic stages: IIIA or higher (40.5% vs. 24.0%). Hispanics more frequently had grade 3 tumors (60% vs. 48%), ER low positive (10% vs. 7%) and ER negative (48% vs. 36%) (p=0.02). No significant differences were noted in triple negative disease or HER2 positive disease. Hispanics were diagnosed at younger average ages (48.9 vs. 53.0 years, p=0.001). No statistically significant differences were noted in time from diagnosis to NAC initiation, completion of chemotherapy, or surgical treatment received (lumpectomy vs. mastectomy, and sentinel node biopsy vs. dissection). Mastectomy was more likely for late-stage disease (OR=2.73, 95% CI: 1.66-4.49, p&amp;lt;0.001); Hispanic women with late-stage disease had 1.09-fold higher odds of receiving mastectomy, but this was non-significant (95% CI: 0.66-1.79). No significant ethnic differences were noted in pCR (p=0.69) or residual tumor cellularity (p=0.63). There was no significant association between residual cellularity and OS. OS rates were similar for Hispanic vs. Non-Hispanic women (HR: 1.15, 95% CI: 0.64-2.08, p=0.63). No difference was noted in ethnicity-based recurrence rates (21.4 vs. 20.1%). Conclusion: Self-identified Hispanic patients were diagnosed at a younger age, presented with higher ER negative and low-positive disease and worse prognostic clinical stage. However, given standard of care chemotherapy, there were no significant differences in their treatment response or outcomes compared to non-Hispanic patients. Citation Format: Sangeetha Prabhakaran, Christopher McNicoll, Vernon S. Pankratz, Nadja Falk, Jacklyn Nemunaitis, Jain Zhou, Payton A. Sandoval-Belt. Differences in disease presentation, and treatment outcomes of neoadjuvant chemotherapy for breast cancer among Hispanics in a minority-serving institution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3686.

Abstract PS5-39: Tumour cellularity size as a biomarker to predict response after neoadjuvant endocrine therapy: Correlation analysis between Ki67 expression and PEPI score

Abstract Background: Neoadjuvant endocrine therapy (NET) is an approach that allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. This evaluation is mainly performed in surgical specimens after NET and it has been used as a research tool to obtain prognostic and predictive information using tumour response to decide adjuvant treatment. In this setting, there are not many validated biomarkers to predict response beyond Ki67 expression and Preoperative Prognostic Index (PEPI score) in NET. The aim of this study is to determine if the tumour cellularity size (TCS) in surgical specimen after NET correlates with PEPI score and Ki67 expression. Methods: Retrospective study of postmenopausal patients with estrogen receptor (ER) positive/HER2 negative resectable breast cancer, treated with an aromatase inhibitor for at least 4 months prior to surgery. Pathological characterization of tumour specimens: Evaluation of the percentage of residual tumour cellularity of formalin fixed paraffin embedded surgical specimens and immunohistochemistry characterization of ER and Ki67. Tumour cellularity size: calculated by combining the percentage of residual tumour cellularity and tumour pathological size. Results: N=104. Tumour characteristics at surgery and breakdown for the calculated PEPI score: table 1. Correlation between the percentage of Ki67 positive cells at surgery and TCS: (r=0.2503) p=0.04 (95% CI, 0.0014 to 0.4700). Correlation between TCS and PEPI score: (r=0.2582) p=0.05 (95% CI, -0.0131 to 0.4940). Conclusions: Tumour cellularity size is a promising biomarker to determine response and prognosis after NET. There is a need to find other biomarkers to predict response after NET. Table 1Pathology/Biomarker statusPEPI score RFS pointsNo. of patientspTNot available (NA)1pT1/T20102pT3/T431pNNA7Negative075Positive322KI67 levelNA10%-2.7%039&amp;gt;2.7%-7.3%131&amp;gt;7.3%-19.7%119&amp;gt;19.7%-53.1%213&amp;gt;53.1%31ER-status Allred scoreNA120-2303-8092PEPI scoreNA190281342533495561PEPI groupNot calculated19I (0 score)28II (1-3 score)42III (≥4 score)15 Citation Format: Joanna Ines Lopez Velazco, María Otaño, Lide Larburu, Ainhara Lahuerta, Kepa Elorriaga, Virginia Segur, Juan Carlos Irizabal, Ana Martínez, Lourdes Jáuregui, Maria M. Caffarel, Ander Urruticoechea. Tumour cellularity size as a biomarker to predict response after neoadjuvant endocrine therapy: Correlation analysis between Ki67 expression and PEPI score [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-39.

Lack of Standardization in the Processing and Reporting of Post-Neoadjuvant Breast Cancer Specimens.

The use of neoadjuvant therapy in the management of early-stage invasive breast cancer is increasing. Residual Cancer Burden and other similar tools use pathologic characteristics of post-neoadjuvant therapy breast tumors to determine long-term outcome. However, there are no standardized guidelines for the pathologic evaluation of these specimens in the routine clinical setting. To assess current practices among Canadian pathologists and pathology assistants with regard to the processing and reporting of post-neoadjuvant therapy breast specimens. An electronic survey was distributed to pathologists and pathology assistants across Canada. Sixty-three responses were obtained. A total of 48% (15 of 31) of surveyed pathologists reported familiarity with the Residual Cancer Burden tool. A total of 40% (25 of 63) of respondents reported a lack of routine use of specimen photography, and 35% (22 of 63) reported a lack of routine use of grossing diagrams. There was significant variation with respect to tumor bed sampling; the most common method was to submit 1 block per centimeter of tumor (20 of 63; 32%). There was also significant variation in the method of measuring residual tumor; the most common method was to measure the largest cross-section of residual tumor (16 of 32; 50%). There is a need for standardization of the evaluation of post-neoadjuvant therapy breast specimens in the routine clinical setting in Canada. We recommend the routine use of specimen mapping, submitting the largest cross section of tumor bed in toto, reporting tumor size as per American Joint Committee on Cancer and Residual Cancer Burden guidelines, and routinely including measurements of residual tumor cellularity and in situ disease in the final pathology report as per Residual Cancer Burden guidelines.

Abstract P2-07-06: Cumulative copy number imbalances after neoadjuvant chemotherapy residual breast tumor is an independent predictor of relapse

Abstract Background: Identifying breast cancer patients after neoadjuvant chemotherapy (NAC) at greatest risk of recurrence would enhance selection of patients who may benefit from novel adjuvant treatments. Patients. 243 stage I-III breast cancer patients who underwent NAC with ≥10% residual tumor cellularity were identified from the MD Anderson Cancer Center and Ben Taub General Hospital, Harris County hospital. Tumor DNA was isolated for DNA copy number using OncoScan CNV FFPE, Affymetrix. Median follow-up was 67.8 months. Continuous residual cancer burden (RCB) scores with CNI data were available for 152 cases. To test if CNIs covering large regions were associated with recurrence after adjusting for prognostic variables and study site, data were summed to a chromosome-arm level. Eleven chromosome arms with false discovery rate &amp;lt;0.05 for breast cancer recurrence were identified. A stepwise multivariable model including age at diagnosis, tumor subtype, histologic grade, pre- and post-treatment stage, study site, and the 11 chromosomal arms were used to fit a parsimonious multivariate model for recurrence. Minimizing the Akaike Information Criterion yielded a final model with post-stage and a 5-arm CNI (5A-CNI) indicator including 2q, 3q, 4q, 10p, and 18p. Tumors were classified on 5A-CNI as 0 [no CNI], 1 [1- 2] and 2 [&amp;gt; 2]. Results. The study population included 76 non-Hispanic White, 89 Hispanic, and 68 African American patients with a mean age of 49.1 years. 105 patients were classified as 5A-CNI-0, 97 as 5A-CNI-1 and 41 as 5A-CNI-2. A higher 5A-CNI score was associated with tumor grade, ER-negative tumors (p&amp;lt;0.002) and tumor subtype (p=0.014). For 5A-CNI scores of 0, 1 and 2, recurrence rates of 14%, 34% and 58.5% were observed, respectively. In the final multivariable model adjusted for post-stage, RCB and study site, when compared to 5A-CNI-0, the hazard of recurrence was elevated for 5A-CNI-1 (HR= 2.27 [95% CI, 1.01-5.1]) and 5A-CNI-2 tumors (HR=7.43 [95% CI, 2.85-19.39]). Further, while the sample size is limiting, of 10 patients who were RCB3 and 5A-CNI-2, 9 relapsed (90%) during follow-up compared to only 6 of 43 (14%) of RCB3 patients with 5A-CNI-0 (p&amp;lt;10-6). For patients with RCB1 or 2, relapse did not differ by 5A-CNI score. Neither race nor ethnicity were found to be independently associated with recurrence or tumor subtype. However, African American, followed by Hispanic patients, were more likely than non-Hispanic White patients to be classified as 5A-CNI-2 (p=0.013). Table 1.Significant difference in distribution of 5 arm CNI classifier by Race/Ethnicity in Study Sample (p =0.013).5A-CNI012Non-Hispanic Whiten=44; 57.9%n=25; 32.9%n=7; 9.2%Hispanicn=32; 36%n=42; 47.2%n=15; 16.9%African Americann=28; 41.2%n=23; 33.8%n=17; 25% Conclusion. The 5A-CNI score in post NAC tumor identifies a patient population with very poor prognosis independent of current clinical prognostic factors including RCB. Validation of these findings may lead to a post NAC genomic test that identifies patients who would benefit from additional treatment Further investigation of the nature of the association between the 5A-CNI score and race/ethnicity, which appears independent of tumor subtype, is warranted. Citation Format: Thompson PA, Brewster A, Tsavachidis S, Armstrong G, Do K-A, Ha M-J, Gutierrez C, Symmans F, Bondy M. Cumulative copy number imbalances after neoadjuvant chemotherapy residual breast tumor is an independent predictor of relapse [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-06.

Measured residual tumor cellularity correlates with survival in neoadjuvant treated pancreatic ductal adenocarcinomas

Measured residual tumor cellularity correlates with survival in neoadjuvant treated pancreatic ductal adenocarcinomas

Abstract P6-09-14: Prognostic significance of a modified residual disease in breast and nodes (mRDBN) algorithm after neoadjuvant therapy for breast cancer

Abstract Background: Patients achieving pathologic complete response to neoadjuvant chemotherapy have excellent disease free and overall survival. For patients with residual disease, the residual disease in breast and lymph node (RDBN) method provides useful prognostic information. RDBN is calculated as follows: 0.2*tumor size (in cm)+lymph node status (0-3) + tumor grade (1-3). pCR, low, intermediate and high risk of recurrence categories correspond to RDBN index of 0, 0.1 to 2.9, 3 to &amp;lt;4.4, and ≥ 4.4, respectively. We hypothesized that the prognostic accuracy of RDBN may be improved by also taking into account the residual tumor cellularity. Methods: Retrospective review of 614 consecutive patients who underwent neoadjuvant therapy for breast cancer was performed. At our institution, tumor size/volume reduction in the breast is determined using the equation: Estimated % tumor size reduction = [(pre-therapy clinical size – “revised” pathology tumor size)/pre-therapy clinical size]*100. “Revised” pathology tumor size is calculated by multiplying the largest dimension of the gross tumor bed by the invasive tumor cellularity of the tumor bed (in comparison to the pre-therapy core biopsy sample). For example, if a 3 cm tumor bed has only 50% cellularity for invasive cancer (in comparison to pre-therapy core biopsy), the revised tumor size is 1.5 cm. Hence, we were able to use the “revised tumor size” for calculating the modified RDBN index (mRDBN). We also used gross tumor bed size for gross RDBN (gRDBN) to compare with mRDBN. mRDBN and gRDBN could be calculated on 459 of the 514 cases. Chi-Square statistical analysis was performed. Results: Mean follow up was 33.1 months (median 31, range 4-70). The results are shown in Table 1 &amp; 2. Table 1. Overall Recurrence and MortalityRDBN Score Category Overall Recurrence Mortality nn (%)RR95% CI; pn (%)RR95% CI; pmRDBN (n=459)High5829 (50.0)19.63[7.22, 53.40]; p=&amp;lt;0.000118 (31.0)16.24[4.97, 53.10]; p=&amp;lt;0.0001Intermed16433 (20.1)7.9[2.86, 21.78]; p=&amp;lt;0.000115 (9.1)4.79[1.41, 16.21]; p=0.006Low803 (3.8)1.47[0.34, 6.42]; p=0.694 (5.0)2.62[0.60, 11.41]; p=0.23pCR1574 (2.5)REF 3 (1.9)REF gRDBN (n=459)High8131 (38.3)15.02[5.49, 41.09]; p=&amp;lt;0.000119 (23.5)12.28[3.74, 40.26]; p=&amp;lt;0.0001Intermed14932 (21.5)8.43[3.05, 23.26]; p=&amp;lt;0.000116 (10.7)5.62[1.67, 18.89]; p=0.003Low722 (2.8)1.09[0.20, 5.82]; p=12 (2.8)1.45[0.25, 8.51]; p=1pCR1574 (2.5)REF 3 (1.9)REF Table 2; Reclassification of gRDBN categoriesgRDBN mRDBN ReclassificationClassificationnLow (%)Intermed (%)High (%)Low7272 (100)0 (0)0 (0)Intermed1498 (5.4)140 (93.9)1 (0.7)High810 (0)24 (29.6)57 (70.4) Conclusions: Both mRDBN and gRDBN provide prognostic information; however, separation of categories is improved with mRDBN (Table 1). mRDBN reclassified 30% of the high risk-gRDBN patients into intermediate risk category with a recurrence rate of 20%, leaving the 'true' high risk subgroup with a revised recurrence rate of 50% (Table 2). RDBN index also identified a group of low risk patients who have prognosis similar to patients with pCR. Citation Format: Farrugia DJ, Landmann A, McAuliffe PF, Diego EJ, Johnson R, Bonaventura M, Soran A, Dabbs DJ, Clark B, Lembersky BC, Puhalla SL, Brufsky A, Jankowitz R, Davidson NE, Ahrendt GM, Bhargava R. Prognostic significance of a modified residual disease in breast and nodes (mRDBN) algorithm after neoadjuvant therapy for breast cancer [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 P6-09-14.

Early detection of chemotherapy-refractory patients by monitoring textural alterations in diffuse optical spectroscopic images.

Changes in textural characteristics of diffuse optical spectroscopic (DOS) functional images, accompanied by alterations in their mean values, are demonstrated here for the first time as early surrogates of ultimate treatment response in locally advanced breast cancer (LABC) patients receiving neoadjuvant chemotherapy (NAC). NAC, as a standard component of treatment for LABC patient, induces measurable heterogeneous changes in tumor metabolism which were evaluated using DOS-based metabolic maps. This study characterizes such inhomogeneous nature of response development, by determining alterations in textural properties of DOS images apparent at early stages of therapy, followed later by gross changes in mean values of these functional metabolic maps. Twelve LABC patients undergoing NAC were scanned before and at four times after treatment initiation, and tomographic DOS images were reconstructed at each time. Ultimate responses of patients were determined clinically and pathologically, based on a reduction in tumor size and assessment of residual tumor cellularity. The mean-value parameters and textural features were extracted from volumetric DOS images for several functional and metabolic parameters prior to the treatment initiation. Changes in these DOS-based biomarkers were also monitored over the course of treatment. The measured biomarkers were applied to differentiate patient responses noninvasively and compared to clinical and pathologic responses. Responding and nonresponding patients demonstrated different changes in DOS-based textural and mean-value parameters during chemotherapy. Whereas none of the biomarkers measured prior the start of therapy demonstrated a significant difference between the two patient populations, statistically significant differences were observed at week one after treatment initiation using the relative change in contrast/homogeneity of seven functional maps (0.001<p<0.049), and mean value of water content in tissue (p=0.010). The cross-validated sensitivity and specificity of these parameters at week one of therapy ranged between 80%-100% and 67%-100%, respectively. Higher levels of statistically significant differences were exhibited at week four after start of treatment, with cross-validated sensitivities and specificities ranging between 80% and 100% for three textural and three mean-value parameters. The combination of the textural and mean-value parameters in a "hybrid" profile could better separate the two patient populations early on during a course of treatment, with cross-validated sensitivities and specificities of up to 100% (p=0.001). The results of this study suggest that alterations in textural characteristics of DOS images, in conjunction with changes in their mean values, can classify noninvasively the ultimate clinical and pathologic response of LABC patients to chemotherapy, as early as one week after start of their treatment. This provides a basis for using DOS imaging as a tool for therapy personalization.

Abstract 1880: Pathologic response pattern of breast cancer after neoadjuvant chemotherapy: its correlation with molecular subtypes

Abstract Background: Several ways to assess pathologic response of breast cancer after neoadjuvant chemotherapy (NAC) are currently used, including Miller-Payne system and residual cancer burden. However, the relationship between pathologic response pattern and molecular subtype of breast cancer is unclear. Methods: We investigated the pathologic response pattern of breast cancer after NAC in each molecular subtype. Female breast cancer patients who received NAC and subsequent breast operation were retrospectively analyzed. The NAC regimen used for breast cancer was primarily anthracycline and taxane-based, depending on the axillary lymph node involvement. We evaluated the molecular subtypes by immunohistochemistry, pretreatment tumor sizes by MRI, absolute invasive tumor cellularities in pretreatment biopsy and operation specimens, pathologic complete response (pCR) rates, posttreatment pathologic tumor sizes, overall residual tumor cellularities, and grades for Miller-Payne system. Results: A total of 119 patients (age: 45.2 ± 9.5 yr) were enrolled. Sixty-six cases were hormone receptor positive (ER or PR positive), 18 cases were HER2 positive (ER and PR negative), and 35 cases were triple negative. There were no significant differences in pretreatment tumor size by MRI and absolute cellularity in biopsy between three groups. After NAC, hormone receptor positive tumors showed the lowest pCR rate (18.2 %) while triple negative tumors showed the highest pCR rate (45.7 %, p=0.013). In patients with residual carcinoma, hormone receptor positive tumors showed the largest ypT size (p=0.016), the least reduction of tumor size (p=0.001), and the least absolute invasive tumor cellularity (p=0.006). Overall residual tumor cellularity and Miller-Payne grade were not significantly different between three groups (p=0.4 and p=0.703, respectively). Conclusion: These results suggest that each molecular subtype of breast cancer shows characteristic pathologic response patterns following NAC. Citation Format: In-Hye Song, Hee Jin Lee, Gyungyub Gong. Pathologic response pattern of breast cancer after neoadjuvant chemotherapy: its correlation with molecular subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1880. doi:10.1158/1538-7445.AM2014-1880

Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck

BackgroundTo investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methodsCetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls. ResultsCetuximab given 24 h before surgery was safe. Ninety percent of patients had 18FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than -25% or less than -50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003). ConclusionsShort-course pre-operative administration of cetuximab is safe and shows a high rate of 18FDG-PET response. 18FDG-PET response was correlated with residual tumour cellularity suggesting that 18FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN.

Residual specimen cellularity after neoadjuvant chemotherapy for breast cancer

Neoadjuvant chemotherapy for breast cancer reduces tumour cellularity, the percentage of the primary tumour area that is composed of invasive tumour cells. Minimal residual tumour cellularity (5 per cent or less of tumour area composed of invasive tumour cells) may be associated with an increased risk of false-negative intraoperative margins. The aim of this study was to evaluate the incidence of minimal residual tumour cellularity after neoadjuvant chemotherapy and its impact on the frequency of false-negative margins and conversion from breast-conserving surgery to mastectomy. The final pathology slides of 510 patients who had surgery after neoadjuvant chemotherapy were reviewed. Of 396 patients with residual invasive breast cancer after neoadjuvant chemotherapy, 100 specimens (25.3 per cent) had minimal residual cellularity; this was more frequent in patients with invasive lobular carcinoma (17.0 versus 5.1 per cent; P < 0.001) or well and moderately differentiated carcinoma (68.0 versus 52.4 per cent; P = 0.007). Among 149 patients who had initial breast-conserving surgery, false-negative intraoperative margin rates were 23 per cent in specimens with minimal and 13.8 per cent in those with higher residual cellularity (P = 0.210). There was no significant difference in the rate of conversion to mastectomy between the groups. Minimal residual cellularity after neoadjuvant chemotherapy occurred in about 25 per cent of specimens, but did not alter the rate of false-negative intraoperative margins.

The pathological response to neoadjuvant chemotherapy with FOLFOX-4 for colorectal liver metastases: a comparative study

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.