Significant Predictor Of pCR Research Articles

Pertuzumab in Combination with Trastuzumab and Docetaxel in the Neoadjuvant Treatment for HER2-Positive Breast Cancer.

This study aims to assess safety and effectiveness of pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant treatment (NeoT) of HER2-positive breast cancer. Two consecutive retrospective cohorts (n = 94, 2012-2015 and 2015-2017) of adult women with HER2-positive breast cancer, receiving NeoT at the breast clinic in Portugal (IPO-Porto), were followed. All patients had surgery and received trastuzumab as adjuvant therapy. The 2012-2015 cohort received doxorubicin, cyclophosphamide, docetaxel plus trastuzumab, whereas the 2015-2017 cohort was treated with the same protocol plus pertuzumab. The 2012-2015 cohort was older (median 53 years), with locally advanced tumors (48.1%), mostly hormone receptor positive (59.3%). The 2015-2017 cohort was younger (median 43 years) with 60% operable tumors. Pathologic complete response (pCR) improved in the second cohort, while maintaining a good safety profile and tolerability. Clinical staging (p = 0.001) and hormone receptor (p = 0.003) were significant predictors of pCR, but not treatment regimen (p = 0.304). Further research with larger samples and longer follow-up is needed to understand the clinical differences. Clinical effectiveness of treatment should also be measured through overall and progression-free survival.

Plasma Profile of Immune Determinants Predicts Pathological Complete Response in Locally Advanced Breast Cancer Patients: A Pilot Study

BackgroundComplex interactions between cancer and the immune system have an impact on disease progression and therapeutic response. Our objective was to evaluate whether circulating immune-related determinants are associated with pathological complete response (pCR) in patients with locally advanced breast cancer (LABC) subjected to neoadjuvant chemotherapy (NACT). Patients and MethodsLuminex technology was used to profile 22 cytokines, 10 chemokines, FGF2, PDGF-BB, VEGF, and Ca15-3/Ca125 glycoforms. Measurements were performed alongside standard hematological determinations on pretreatment plasma samples from 151 patients including 41 cases with pCR assessed following RECIST criteria. ResultsRandom Forest model analysis selected platelets, eotaxin, IFN-γ, IP10, and TGFβ2 as significant predictors of pCR. These immune-related features were combined into a quantitative score predictive of pCR. In patients who scored 0 or 1, none had pCR; the pCR frequency increased in relation to the score value (23.5%, 41.2%, and 78.6%, in score groups 2, 3, and 4, respectively). At multivariable logistic analysis, the pCR score was highly significant (odds ratio = 3.15 per unit increment; CI: 1.85-5.38; P < .0001); among clinical covariates (age, menopausal status, tumor stage, IHC subtype, Ki-67, CA15.3, and CA125), only Ki-67 was statistically significant (P = .013). ConclusionThis explorative study aimed to lay the conceptual and practical foundation that a distinctive pattern of the immune determinant blood signature at diagnosis of LABC significantly correlates with the patient's response to NACT and provides the groundwork for larger studies that could lead to a minimally invasive tool for personalized medicine.

Trimodality therapy for locally advanced esophageal squamous cell carcinoma: the role of volume-based PET/CT in patient management and prognostication.

To evaluate the role of positron emission tomography/computed tomography (PET/CT) in predicting pathologic complete response (pCR) and identify relevant prognostic factors from clinico-imaging-pathologic features of locally advanced esophageal squamous cell carcinoma (eSCC) patients undergoing trimodality therapy. We evaluated 275 patients with eSCCs of T3-T4aN0M0 and T1-T4aN1-N3M0 who received trimodality therapy. We correlated volume-based PET/CT parameters before and after concurrent chemoradiation therapy with pCR after surgery, clinico-imaging-pathologic features, and patient survival. pCR occurred in 75 (27.3%) of 275 patients, of whom 61 (80.9%) showed 5-year survival. Pre-total lesion glycolysis (pre-TLG, OR = 0.318, 95% CI 0.169 to 0.600), post-metabolic tumor volume (post-MTV, OR = 0.572, 95% CI 0.327 to 0.999), and % decrease of average standardized uptake value (% SUVavg decrease, OR = 2.976, 95% CI = 1.608 to 5.507) were significant predictors for pCR. Among them, best predictor for pCR was pre-TLG with best cutoff value of 205.67 and with AUC value of 0.591. Performance status (HR = 5.171, 95% CI 1.737 to 15.397), pathologic tumor size (HR = 1.645, 95% CI 1.351 to 2.002), pathologic N status (N1, HR = 1.572, 95% CI 1.010 to 2.446; N2, HR = 3.088, 95% CI 1.845 to 5.166), and post-metabolic tumor volume (HR = 1.506, 95% CI 1.033 to 2.195) were significant predictors of overall survival. Pre-TLG, post-MTV, and % SUVavg decrease are predictive of pCR. Additionally, several clinico-imaging-pathologic factors are significant survival predictors in locally advanced eSCC patients undergoing trimodality therapy.

Abstract PS10-33: Analysis of factors associated with pathological complete response (pCR) in patients with HER2+ breast cancer receiving neoadjuvant chemotherapy

Abstract Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) is associated with improved survival outcomes among women with HER2 positive (HER2+) breast cancer. We aimed to analyze the clinical, pathological and molecular factors associated with pCR in our series of HER2+ breast cancer patients. Methods: Between 2009 and 2019, breast cancer patients receiving NAC at our centre were enrolled in a prospective database. For this study we selected women with HER2+ unilateral breast cancer stages II or III who received anthracycline-taxane NAC regimens (with trastuzumab given concurrently with the taxane) and subsequently underwent breast and axillary surgery with curative intent. Medical charts of these 161 women were retrospectively reviewed to determine what clinical, pathological and molecular characteristics were associated with pCR using bivariate and multivariate analysis. Results: Of the 161 HER2+ women median age at diagnosis was 49 years (range 25-78) with 90 (56%) women under age 50. Total of 104 (65%) tumors were stage II, 108 (67%) expressed estrogen and/or progesterone receptors, 139 (86%) had HER2 3+ expression by immunohistochemistry (IHC) and 22 (14%) had HER2 IHC 2+ expression with amplified HER2 on fluorescence in situ hybridization (FISH) test. The NAC regimens were: Doxorubicin-Cyclophosphamide-Paclitaxel for 83 (52%) and Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel for 78 (48%) women. A total of 73 patients [45%; 44/108 HR+ (41%) and 29/53 HR- (55%)] achieved pCR (p=0.94). pCR rate among HER2 IHC 3+ tumors was 69/139 (50%), while for HER2 IHC 2+ tumors was 4/22 (18%). On bivariate analysis HER2 IHC 3+, absence of estrogen receptors and absence of progesterone receptors were predictive of pCR, while age, menopausal status, histologic subtype, tumor grade and NAC regimen were not. In the multivariate model only HER2 IHC 3+ expression remained a significant predictor of pCR (OR =4.443, 95% CI 1.376 - 14.344). Conclusion: Our analysis suggests that for HER2+ breast cancers treated with NAC with anthracycline-taxane and trastuzumab, HER2 IHC 3+ expression is associated with a higher rate of pCR compared to HER2 IHC 2+ expression with FISH amplification. Further analysis in a larger cohort is warranted. Citation Format: Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni MM Mata, Anthony Lott, Maria Romero, Sharon Lemon-Wong, Althea VanMassop, Xingshan Cao, William Tran, Rossanna Pezo. Analysis of factors associated with pathological complete response (pCR) in patients with HER2+ breast cancer receiving neoadjuvant chemotherapy [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 PS10-33.

Triple-Positive Breast Carcinoma: Histopathologic Features and Response to Neoadjuvant Chemotherapy.

It is unclear whether HER2+ tumors expressing both estrogen receptor (ER) and progesterone receptor (PR), that is, triple-positive breast carcinomas (TPBCs), show unique morphologic and clinical features and response to neoadjuvant chemotherapy (NAC). To study the morphologic and immunohistochemical features of TPBCs from patients who underwent NAC. We retrospectively reviewed core biopsy and post-NAC slides of 85 TPBCs. H-scores were calculated for ER and PR. HER2 slides and fluorescence in situ hybridization (FISH) reports were reviewed. Residual cancer burden was calculated for post-NAC specimens. Eighty-one of the 85 tumors (95.3%) showed ductal histology, 3 (3.5%) were invasive lobular carcinomas, and 1 (1.2%) showed mixed ductal and lobular features. A subset showed mucinous (n = 7, 8.2%), apocrine (n = 5, 5.9%), and/or micropapillary (n = 4, 4.7%) differentiation. Fifty-four TPBCs (63.5%) showed high ER expression (H-score >200), including 27 (31.8%) with high expression of ER and PR. Fifty-two tumors (61.1%) showed HER2 3+ staining. Mean HER2/CEP17 ratio by FISH was 3.6 (range, 2-12.2) and mean HER2 signals per cell was 8 (range, 3.7-30.4). Pathologic complete response (pCR) rate was 35.3% (30 of 85). HER2 3+ staining was the only significant predictor of pCR on multivariate analysis (odds ratio = 9.215; 95% CI, 2.401-35.371; P < .001). The ER/PR expression did not correlate with response to therapy. TPBCs are heterogeneous with some showing mucinous, lobular, or micropapillary differentiation. The pCR rate of TPBCs is similar to that reported for ER+/PR-/HER2+ tumors. HER2 overexpression by IHC was associated with significantly better response to therapy and may help select patients for treatment in the neoadjuvant setting.

A multicenter phase II trial of the combination cisplatin/ docetaxel/durvalumab/tremelimumab as single-cycle induction treatment in locally advanced HNSCC (CheckRad-CD8 trial).

6519 Background: PD-1/PD-L1 inhibitors are efficient in head and neck squamous cell cancer (HNSCC). Combination with anti-CTLA4 agents may enhance anti-tumor activity compared to anti-PD-1/PD-L1 monotherapy in different tumor types. In the CheckRad-CD8 trial the typical induction treatment consisting of Cisplatin/Docetaxel was combined with Durvalumab/Tremelimumab. Patients with pathological complete response (pCR) in the re-biopsy after induction treatment or at least 20% increase of intratumoral CD8 density in the re-biopsy compared to baseline entered radioimmunotherapy with concomitant Durvalumab/Tremelimumab. Methods: In this prospective multicenter phase II trial, patients with HNSCC stage III-IVB received a single cycle of Cisplatin 30mg/m² d1-3, Docetaxel 75mg/m² d1, Durvalumab 1500mg fix dose d5 and Tremelimumab 75mg fix dose d5. Objectives of this interim analysis were to quantify the effect of the induction treatment on intratumoral CD8 density and the pCR rate and to generate safety data. Results: Between Sep 2018 and Dec 2019, 57 patients were enrolled. Median age was 59 years, 22 patients (37%) were current smokers, 27 patients (47%) had oropharyngeal tumors (52% p16 positive). The median pre-treatment intratumoral CD8 density was 335 CD8+ cells/mm². After induction treatment 27 patients (47%) had a pCR in the re-biopsy and further 25 patients (44%) had a relevant increase of intratumoral CD8+ cells (median increase by factor 3.0). Response according to RECIST criteria was CR in 1 (2%), PR in 19 (33%) and SD in 20 patients (35%) (17 patients not evaluable). Adverse events (AE) grade 3-4 appeared in 39 patients (68%) and mainly consisted of leucopenia (43%) and infections (28%). 6 patients (11%) developed grade 3-4 immune-related AEs. In multivariable analysis the intratumoral CD8 density was the only independently significant predictor of pCR (odds ratio 1.0013 per cell/mm², 95%-CI 1.00023-1.0023, p=0.017). 42 patients (74%) continued with Durvalumab/ Tremelimumab concomitant to radiotherapy. Conclusions: Single cycle induction treatment with Cisplatin/Docetaxel/Durvalumab/Tremelimumab is feasible and achieves a high pCR rate. CD8 density may have a predictive role for further treatment planning in locally advanced HNSCC. Clinical trial information: NCT03426657 .

Multi-Gene Prognostic Signatures and Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in ER-positive, HER2-negative Breast Cancer Patients.

Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson’s correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients.

Abstract P1-10-07: The presence of ductal carcinoma in situ in core needle biopsy and microcalcifications on mammography in TNBC is associated with a lower pCR and worse long term outcome

Abstract Purpose Predictors for pathological Complete Response (pCR) in TNBC are very important given pCR is considered a surrogate marker for breast cancer-related survival. Associated DCIS in TNBC (accom-DCIS) as well as presence of microcalcifications on initial mammography (micro-MG) have been correlated with Androgen Receptor positive TNBC, known to achieve lower pCR rates. We aim to investigate the predictive impact of accom-DCIS and micro-MG on pCR. We also validated known clinico-pathological predictors for pCR. Long term outcome was analyzed for pCR and accom-DCIS. Methods A retrospective cohort study (diagnosed 1/1/2000 - 31/12/2017) of prospectively registered consecutively treated TNBC patients was performed. TNBC was defined as IHC-ER&amp;lt;1%, IHC-PR&amp;lt;1% and IHC-HER2 0-1+ and FISH negative if HER2 IHC 2/3+. All patients had standard of care neoadjuvant chemotherapy (NAC) in our hospital. Patients with at least 2 years of documented follow up and only TNBC of no special type on core needle biopsy (CNB) were included. We evaluated the predictive value of patient factors (age, BMI, symptomatic/screening-detected), imaging (micro-MG) and tumor related factors as reported in the pathology-report (grade, cT, focality, cN, lymphovascular invasion, accom-DCIS) for pCR (defined as pT0-TisN0). We used distant relapse rate and death to evaluate outcome. The Cox proportional hazards model was used to analyze the effect of pCR and accom-DCIS on distant relapse rate as well as overall survival (OS) in a multivariate model (corrected for size, nodal state, grading). Results are presented as hazard ratios (HR) with 95% confidence intervals (CI). Results The study contains 219 patients; accom-DCIS was reported in 53/219 (24.2%) CNB’s; pCR was achieved in 90/219 (41,1%). Patient related factors were comparable in patients who achieved pCR and those who had residual disease. Unifocal, smaller clinical size tumors and high tumor grade were significant predictors for pCR in our series. Analysis of 194 available mammographies showed micro-MG in 63/194 (32.5%). Micro-MG predicted for residual disease after NAC [HR = 3.350; 95% CI (1.708 - 6.569), p=0.005]. Accom-DCIS was a strong negative predictor of pCR [HR = 3.333; 95% CI (1.558 - 7.143), p=0.002)] and was associated with more distant relapse and worse survival [HR = 2.664; 95% CI (1.575 - 4.505), p=0.003]. pCR was strongly associated with a lower distant relapse rate and a better OS [HR = 2.210; 95% CI (1.282 - n3.811), p=0.004]. In the 129 cases without pCR, remaining tumor size [HR = 1.019; 95% CI (1.012 - 1.025), p=&amp;lt; 0,001), ypN [HR = 1.917; 95% CI (1.539 - 2.388), p=&amp;lt; 0,001) and presence of LVI [HR = 3.720; 95% CI (2.057 - 6.728), p=&amp;lt; 0,001] significantly predicted for secondary metastasis. There was only a trend towards more distant relapses if accom-DCIS was found in the resection specimen in those who had residual disease [HR = 1.347; 95% CI (0.780 - 2.325), p=0.2855]. Conclusion Presence of accom-DCIS in CNB as well as micro-MG predicts for less pCR in TNBC. Accom-DCIS in CNB is associated with more distant relapse and worse OS. For accom-DCIS on resection specimen, there was only a tendency towards more distant relapses. Citation Format: Jan Ardui, Sophie Vandamme, Chantal Van Ongeval, Giuseppe Floris, Hava Izci, Hans Wildiers, Kevin Punie, Tatjana Geukens, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Annouschka Laenen, Caroline Weltens, Hilde Janssens, Patrick Neven. The presence of ductal carcinoma in situ in core needle biopsy and microcalcifications on mammography in TNBC is associated with a lower pCR and worse long term outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-07.

Abstract P1-02-04: Contrast-enhanced ultrasonography after two cycles of chemotherapy predicts the outcome of neoadjuvant chemotherapy in triple-negative breast cancer

Abstract Background: Contrast-enhanced ultrasonography (CEUS) allows a thorough visualization of the intra-tumoral blood flow. This study aimed to determine if CEUS can predict the early effects of neoadjuvant chemotherapy (NAC) on breast cancer. Patients and Methods: We evaluated 93 patients with triple-negative type (ER-negative and HER2-negative, n= 30), HER2-positive (HER2-positive and any ER, n= 34), and luminal type (ER-positive and HER2-negative, n= 29) invasive breast cancer who underwent NAC between September 2012 and March 2019. Ultrasonography (US) and CEUS were performed before NAC and after two cycles of NAC. All patients underwent either mastectomy or breast-conserving surgery after NAC. To objectively evaluate CEUS findings, the ascending slope (AS) in perfusion parameters of CEUS was calculated using time-intensity curves based on enhancement intensity and temporal changes. The changes of maximum tumor diameter in US (ΔUS) and the changes of AS in perfusion parameters of CEUS (ΔAS) were measured in the primary tumor. Results: Thirty-seven (39.8%) patients achieved pathological complete response (pCR). In triple-negative breast cancer, both of ΔUS and ΔAS showed a significant decline with pCR, but there were no significant differences in ΔUS and ΔAS in the luminal-type and HER2-positive breast cancer. We set cutoffs of the ΔUS (-37%, AUC 0.742) and ΔAS (-26%, AUC 0.823) for predicting pCR on the basis of their ROC curves. ΔUS (OR 8.75, p=0.017) and ΔAS (OR 21.3, p=0.0001) in univariate analysis and ΔAS (OR 16.1, p=0.009) in multivariate analysis were significant predictors for pCR in triple-negative breast cancer. The sensitivity, specificity, and accuracy for predicting pCR in triple-negative breast cancer were 0.70, 0.79, and 0.76 in ΔUS and 0.80, 0.84, and 0.83 in ΔAS, respectively. The sensitivity, specificity, and accuracy of ΔAS were greater than those of ΔUS for predicting pCR. Conclusions: CEUS may serve as a new important diagnostic modality when planning therapeutic strategies, for patients with triple-negative breast cancer who received NAC. univariate analysis and multivariate analysis for pCR in triple-negative breast cancerCharacteristicUnivariate logistic analysisMultivariate logistic analysisOR95%CIpOR95%CIpAge, &amp;lt;50 vs ≧500.960.21-4.341.0000Clinical T, T1 vs T2-40.900.13-6.461.0000Clinical N, Negative vs Positive0.360.08-1.720.2635Nuclear Grade, 3 vs 1-20.750.14-3.901.0000Ki67, &amp;lt;20 vs ≧ 20--0.2685US findingsΔUS(%), ≧-37 vs ←378.751.53-50.110.01695.800.73-58.390.1004ΔAS(%), ≧-26 vs ←2621.332.94-154.550.001316.142.28-177.580.0096 Citation Format: Mai Nishina, Norio Masumoto, Akiko Kanou, Kayo Fukui, Yuri Kimura, Ai Amioka, Tomoko Itagaki, Shinsuke Sasada, Akiko Emi, Takayuki Kadoya, Morihito Okada. Contrast-enhanced ultrasonography after two cycles of chemotherapy predicts the outcome of neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-02-04.

Evaluation of the 12-Gene Molecular Score and the 21-Gene Recurrence Score as Predictors of Response to Neo-adjuvant Chemotherapy in Estrogen Receptor-Positive, HER2-Negative Breast Cancer

BackgroundNeo-adjuvant chemotherapy (NaCT) facilitates complete surgical resection in locally advanced breast cancer. Due to its association with improved outcome, complete pathologic response (pCR) to neo-adjuvant treatment has been accepted as a surrogate for long-term outcome in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, or luminal B breast cancer patients. In contrast, NaCT is effective in only ~ 7–10% of estrogen receptor (ER)-positive, HER2-negative disease. Response biomarkers would enable such patients to be selected for NaCT.MethodsTwo commercially available breast cancer prognostic signatures [12-gene molecular score (MS) and the 21-gene Recurrence Score (RS)] were compared in their ability to predict pCR to NaCT in ER-positive, HER2-negative breast cancer in six public RNA expression microarray data sets. Scores were approximated according to published algorithms and analyzed by logistic regression.ResultsExpression data were available for 764 ER-positive, HER2-negative breast cancer samples, including 59 patients with pCR. The two scores were well correlated. Either score was a significant predictor of pCR (12-gene MS p = 9.4 × 10−5; 21-gene RS p = 0.0041). However, in a model containing both scores, the 12-gene MS remained significant (p = 0.0079), while the 21-gene RS did not (p = 0.79).ConclusionsIn this microarray study, two commercial breast cancer prognostic scores were significant predictors of response to NaCT. In direct comparison, the 12-gene MS outperformed the 21-gene RS as a predictive marker for NaCT. Considering pCR as surrogate for improved survival, these results support the ability of both scores to predict chemotherapy sensitivity.

279P - Ring-like uptake appearance on dedicated breast positron emission tomography before chemotherapy predicts outcome of neoadjuvant chemotherapy in breast cancer

BackgroundDedicated breast positron emission tomography (DbPET) with 18F-fluorodeoxyglucose (FDG) can detect intratumoral heterogeneity. In a previous study, we proved that intratumoral heterogeneous distribution of FDG on DbPET is significantly related to a high nuclear grade and high Ki-67 proliferation index; we also proved that DbPET is useful for predicting residual breast tumors after neoadjuvant chemotherapy (NAC). This study included patients with breast cancer who exhibited a ring-like uptake without central FDG accumulation on DbPET and aimed to evaluate whether the uptake can predict the effects of NAC in patients with breast cancer. MethodsThe study included 83 consecutive patients with breast cancer who subsequently underwent DbPET and NAC between August 2016 and March 2019 and evaluated the relationship between pathological response to NAC and clinicopathologic factors (clinical T1: n=14; clinical N0: n=33; nuclear grade 1 or 2: n=22; Ki67 ≥ 20: n=78; ER positive: n=52; and HER-2 positive: n=32), such as intratumoral heterogeneous distribution of FDG (positive: n=54) and ring-like uptake without central FDG accumulation (positive: n=11) on DbPET images. ResultsSurgical pathological findings obtained after the NAC indicated pathological complete response (pCR) and non-pCR in 32 (38.6%) and 51 (61.4%) patients, respectively. For all the patients, significant predictors for pCR were identified in univariate analyses (clinical T: odds ratio = 3.60, p=0.03; clinical N: odds ratio = 2.48, p=0.049; HER-2 overexpression: odds ratio = 2.72, p=0.03; and ring-like uptake: odds ratio = 5.33, p=0.01) and multivariate analyses (HER-2 overexpression: odds ratio = 3.29, p=0.03; ring-like uptake: odds ratio = 17.6, p=0.0006) (Table).Table279P Univariate and multivariate logistic analysis of significant predictive clinicopathological factors for pCRTableCharacteristicUnivariate logistic analysisMultivariate logistic analysisOR95%CIpOR95%CIpAge, <50 v≥501.380.57-3.380.481.970.65-5.980.23Clinical T, T1 v T2- T43.601.11-12.90.033.860.97-15.40.06Clinical N, Negative v Positive2.481.00-6.280.0492.860.97-8.420.06Nuclear Grade, 3 v 1-21.490.54-4.380.451.650.41-6.700.48Ki67, ≥20 v<202.640.37-52.80.361.340.11-16.50.82ER, Negative v Positive1.250.50-3.120.631.050.33-3.340.93HER-2, Positive v Negative2.721.09-6.940.033.291.11-9.730.03Intratumoral heterogenity, Positive v Negative1.500.59-3.780.391.690.43-6.570.45Ring-like uptake, Positive v Negative5.331.40-26.10.0117.62.27-136.20.006 ConclusionsRing-like uptake on DbPET provides predictive value for evaluating pCR to NAC in patients with breast cancer and might inform therapeutic decisions. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

257P - Multi-gene prognostic signatures and prediction of pathological complete response of ER-Positive HER2-negative breast cancer patients to neo-adjuvant chemotherapy

BackgroundDetermining which early stage breast cancer patients should receive chemotherapy is an important clinical and economic issue. Chemotherapy has many adverse side effects, impacting on quality of life, along with significant economic consequences. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective overtreatment. The aim of this work is to assess if the OncoMasTR (OM) signature can predict pathological complete response (pCR) to neo-adjuvant chemotherapy, and to compare its predictive value with EndoPredict (EP) and Oncotype DX (RS). MethodsGene expression datasets derived from breast cancer patients that had pre-treatment biopsies, received neo-adjuvant chemotherapy and an assessment of pCR were obtained from GEO (GSE16716, GSE20271, GSE25066, GSE32646, GSE34138, GSE41998, GSE22226). Patients with ER-positive, HER2-negative disease and pCR data were selected. OM, EP and RS numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. Association with pCR was estimated using logistic regression. ResultsA total of 813 patients with 66 pCR events were included in the analysis. OM, EP and RS prognostic scores were moderately well correlated according to the Pearson’s correlation coefficient: OM vs EP (min=0.44; mean=0.67; max=0.81), OM vs RS (min=0.34; mean=0.62; max=0.79), and RS vs EP (min=0.55; mean=0.79; max=0.89). Significant predictors of pCR with p-values of 0.0001 for all three signatures. Odds ratios for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude and not significantly different: OM 1.66 (1.29 to 2.16), EP 1.76 (1.37 to 2.27), RS 1.84 (1.44 to 2.35). ConclusionsIn this in silico analysis, OM, EP and RS prognostic scores were significantly predictive of pCR to neo-adjuvant chemotherapy in ER-positive, HER2-negative breast cancer. Optimal stratification for neo-adjuvant chemotherapy offers the opportunity for personalised care, improved therapy response rates, and reduced ineffective treatment and costs. Legal entity responsible for the studyUniversity College Dublin. FundingThe EI and from the European Union’s Horizon 2020 research and innovation programme under the Marie Slodowska-Curie grant agreement No. 713654. DisclosureThe author has declared no conflicts of interest.

Pathologic complete response rate according to HER2 detection methods in HER2-positive breast cancer treated with neoadjuvant systemic therapy.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are known to have significant clinical and pathological response to neoadjuvant systemic therapy (NST). The aim of this study was to identify factors associated with pathological complete response (pCR), defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is ypN0), among patients with HER2-positive breast cancer and to compare pCR rates between breast cancers with HER2 protein overexpression by immunohistochemistry (IHC) versus HER2 gene amplification by fluorescence in situ hybridization (FISH) in the absence of protein overexpression by IHC. We conducted a retrospective review of HER2-positive breast cancer patients treated with NST and surgery at Memorial Sloan Kettering Cancer Center between January 2013 and May 2018. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were assessed according to the 2018 ASCO/CAP guidelines. During the study period, 560 patients were identified. Of 531 patients with IHC results available, 455 patients had HER2 IHC 3+, and 76 had IHC < 3+ but HER2 amplification detected by FISH. The overall pCR rate was 59% (330/560). The pCR rate among patients with HER2 protein overexpression (IHC 3+) was 67%, compared to 17% among patients with HER2 amplification by FISH (IHC < 3+). On univariate and multivariate analyses, HER2 protein overexpression by IHC (IHC 3+) was a significant predictor of pCR, along with grade 3 histology, PR-negative status, and dual anti-HER2 therapy. Although both HER2 IHC and FISH are standard HER2 testing methods in breast cancer, achievement of pCR is associated with HER2 IHC expression level, among other factors.

Abstract P6-02-15: TILs-US score using ultrasonography before chemotherapy predicts the outcome of neoadjuvant treatment in HER2 positive breast cancer

Abstract Purpose Tumor-infiltrating lymphocytes (TILs) have been reported to be predictive factors of therapeutic effect in neoadjuvant chemotherapy (NAC). And while TILs can be evaluated in preoperative biopsy tissue, heterogeneous distribution of TILs requires examination of all biopsied tissue samples. We gave scores to preoperative US images with characteristics indicative of LPBC and attempted to apply these for diagnostic prediction of LPBC. In this study, TILs-US score based on US images obtained before chemotherapy was examined as an alternative method to LPBC evaluated on preoperative biopsy tissues (pre-LPBC) for application in the prediction of pathological complete response (pCR). Methods We evaluated 67 patients in triple negative type (n=22), HER-2 positive (n=33), luminal type (n=12) with invasive breast cancer who underwent neoadjuvant chemotherapy between March 2012 and July 2016. Ultrasonography (US) was performed before NAC. All patients were treated by either mastectomy or breast-conserving surgery after NAC. Stromal lymphocytes were evaluated on preoperative biopsy tissues. Breast cancer samples with ≥ 50% stromal TILs were defined as LPBC. There were 39 cases of LPBCs and 122 cases of non-LPBCs in pathological specimens using a biopsy before NAC. TILs-US score (0˜7 point) was calculated from US before NAC. We set TILs-US score cut-offs for predicting LPBC at 4 points based on our previous data. Based on clinicopathological factors including TILs-US scores based on US and LPBC indicators before NAC, determinants useful for prediction of LPBC were examined. Results The surgical pathological findings after NAC indicated pCR and non-pCR in 32 (47.8 %) and 35 (52.2 %) patients. There were significant predictors for pCR in univariate (Clinical N: OR 2.83, p=0.043; HER-2: OR4.80, p=0.002; TILs-US score: OR 2.83, p=0.04) and multivariate analyses (HER-2: OR 6.42, p=0.009) in all breast cancer. There were not significant predictors for pCR in univariate and multivariate analyses in triple negative breast cancer. While, there were significant predictors for pCR in univariate (TILs-US score: OR17.5, p=0.002) and multivariate analyses (TILs-US score: OR 82.8, p=0.02) in HER2 positive breast cancer. Multivariate analysis for prediction of pCR in HER2 positive breast cancer Multivariate logistic analysisCharacteristicOR,95%CI,PAge, &amp;lt;50 v ≥5012.7,0.84-191.8,0.07Clinical T, T1-2 v T3- T416.5,0.23-1177.2,0.20Clinical N, Negative v Positive1.74,0.16-19.2,0.65Nuclear Grade, 3 v 1-22.57,0.12-55.7,0.55ER, Negative v Positive3.01,0.16-55.2,0.46LPBC, ≥50 % v &amp;lt;50 %3.52,0.22-55.2,0.37TILs-US score, ≥4 v &amp;lt;382.8,2.15-3186.8,0.02 Conclusions In patients with HER2 positive breast cancer, TILs-US score can predict the therapeutic effectin neoadjuvant chemotherapy (NAC) and help with the development of appropriate treatment plans. Citation Format: Masumoto N, Kadoya T, Kanou A, Fukui K, Shiroma N, Sueoka S, Suzuki E, Noriko G, Sasada S, Emi A, Haruta R, Kataoka T, Arihiro K, Okada M. TILs-US score using ultrasonography before chemotherapy predicts the outcome of neoadjuvant treatment in HER2 positive breast cancer [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 P6-02-15.

Abstract P3-10-25: Clinicopathologic factors associated with pCR to neoadjuvant anti-HER2-directed chemotherapy

Abstract Background: While the use of neoadjuvant therapy has become the standard of care in certain locally advanced breast cancers, questions remain regarding the optimal chemotherapeutic regimen as well as biologic and patient-specific predictors of pathologic complete response. In this study, we examined patient and tumor-specific characteristics associated with increased prediction of pathologic complete response (pCR) to neoadjuvant anti-HER2-directed chemotherapy. Methods: 204 patients who received neoadjuvant anti-HER2-directed chemotherapy at our institution from 2006-2016 were included in this retrospective study. Univariate analyses were performed to analyze the relationships of multiple clinical and pathologic features to pCR rate. Multivariate analysis was also performed to evaluate the relative impact of specific pathologic characteristics on pCR rate. Results: Among 204 patients with HER2 overexpressing breast cancers treated with neoadjuvant chemotherapy, 52.7% achieved pCR. Pathologic complete response was positively associated with high tumor grade (61.0% grade 3 in pCR group vs 39.0% in non-pCR group, P=0.23) and high Ki67 index (mean Ki67 59.1 in pCR group vs 47.4 in non-pCR; P= 0.015). It was also associated with HER2 IHC 3+ (57.1% in pCR group vs 42.9% in non-pCR, p=0.029), HER2 copy number (mean copy number 16.8 in pCR group vs 12.4 in non-PCR, p-0.004), and HER2/CEP 17 ratio (mean ratio 6.42 in pCR group vs 5.17 in non-pCR; P= 0.046). Rates of HER2 FISH positivity were equal in the pCR and non-pCR groups (50.8% vs 49.2%, p=0.062). Multivariate analysis demonstrated that higher Ki67 index and higher HER2/CEP17 ratio are significant predictors of pCR after adjusting for other covariates (odds ratio for Ki67 1.03 (1.06-1.49), p=0.002; for HER2/CEP17 ratio OR 1.26 (1.06-1.49), p=0.009). Conclusions: In HER2 positive breast cancers, a higher Ki67 index as well as higher HER2/CEP17 ratios are associated with an increased pCR rate and may be useful as predictors of response prior to neoadjuvant therapy. Our results also demonstrate HER2 IHC to be a stronger predictor than HER2 FISH of response to upfront therapy. Larger studies would be useful as this association, if confirmed, may have relevance to clinical practice. Citation Format: Meisel JL, Suo A, Taylor CE, Zhang C, Li X. Clinicopathologic factors associated with pCR to neoadjuvant anti-HER2-directed chemotherapy [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 P3-10-25.

Predicting the pathologic complete regression with hematologic markers during neoadjuvant chemoradiotherapy in the locally advanced rectal cancer.

583 Background: The present study aimed to evaluate the hematologic markers for predicting the pathologic complete regression during and after neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. Methods: Total 297 patients with rectal cancer underwent neoadjuvant CRT followed by surgical resection and performed complete blood counts (CBC) serially during and after CRT. The timepoints of CBC were before CRT (pre-), three weeks after the day of starting CRT (intra-), and four weeks after CRT (post-). We calculated the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte (NLR), derived neutrophil-to-lymphocyte (dNLR) using the serial CBC test. The ratio of change in PLR (cPLR), NLR (cNLR), and dNLR (cdNLR) was calculated as the change of value/pre-value. Chi-square and T-test for univariate analysis and multivariate logistic regression were performed to identify the significant predictor for pCR. Receiver operating characteristics (ROC) analysis was used to compare the predictive values. Results: The overall rate of pCR was 15.9%. The Pre-Hb, pre-NLR, intra-PLR, intra-NLR, intra-cPLR, intra-cNLR, post-WBC, post-Hb, and post-cPLR were significantly different between patients with pCR and no pCR. In the multivariate logstic regression, pre-Hb (OR 1.456 p-value .026), intra-cPLR (OR 4.949, p-value &lt; .001), post-WBC (OR 0.664, p-value .008), and post-PLR (OR 1.011 p-value .001) were significant predictors for pCR. In the comparison of ROCs, intra-cPLR was the most accurate predictor for pCR among the hematologic variables (AUC = 0.74, p ≤ .001). Conclusions: Change of PLR during neoadjuvant CRT is the clinically applicable and significant predictor for pCR with high negative predictive value in the patients with LRC.

Predicting Pathological Complete Regression with Haematological Markers During Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer.

This study evaluated the efficacy of haematological markers for predicting the pathological complete regression (pCR) during and after neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). A total of 297 patients with LARC underwent neoadjuvant CRT followed by surgical resection. Complete blood counts (CBCs) were performed before CRT, 3 weeks after the start of CRT (intra-therapy), and 4 weeks after CRT. Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were calculated using the serial CBC test. The ratio of change in PLR (cPLR) and NLR (cNLR) was calculated as the increase from the pre-therapy value to intra-therapy or post-therapy value divided by the pre-therapy value. Chi-square and t-test for univariate analysis and multivariate logistic regression were performed to identify significant predictors for pCR. Receiver operating characteristic (ROC) analysis was used to compare predictive values. The overall rate of pCR was 15.9%. Pre-therapy high haemoglobin and low NLR; intra-therapy high PLR, high NLR, high cPLR, and high cNLR; and post-therapy low white blood cell count (WBC), high haemoglobin, and high cPLR were significantly associated with pCR. In multivariate logistic regression, pre-therapy high haemoglobin [odds ratio (OR)=1.500, p=0.016], high intra-therapy PLR (OR=1.006, p=0.011), high intra-therapy cPLR (OR=4.948, p<0.001), and low post-therapy WBC (OR=0.639, p=0.003) were significant predictors for pCR. ROC analysis showed that high intra-therapy cPLR was the most accurate predictor of pCR (area under the curve=0.741). Changes of PLR during neoadjuvant CRT for LARC are significant predictors of pCR.

EarlyR signature predicts response to neoadjuvant chemotherapy in breast cancer

BackgroundEarlyR gene signature uses ESPL1, SPAG5, MKI67, PLK1 and PGR to classify ER+ breast cancer (ER+ BC) into EarlyR-Low, EarlyR-Int, and EarlyR-High risk strata and is prognostic in patients treated with adjuvant chemotherapy. The ability of EarlyR to predict pathological complete response (pCR) and long-term survival following neoadjuvant chemotherapy (NACT) is evaluated herein. MaterialsThe ability of EarlyR gene signature to predict pCR was assessed in publicly available Affymetrix microarray datasets (Cohort A; n = 659; 74 pCR events) derived from NACT-treated ER+ BC patients. Distant relapse-free survival (DRFS) results were analyzed in patients treated with NACT and adjuvant hormone therapy (AHT) (n = 281) and compared with patients treated with AHT alone (n = 455) (Cohort B; n = 736; 142 events). ResultsIn cohort A, EarlyR was a significant predictor of pCR (p = 5.8 × 10−11) (EarlyR-Low, n = 400, pCR = 40, 5%; EarlyR-Int, n = 69, pCR = 7, 15% and EarlyR-High, n = 190, pCR = 47, 24%). In EarlyR-Low of Cohort B, the 5-year DRFS was not significantly (p = 0.55) different between NACT + AHT [0.81 (95%CI 0.73–0.90)] and AHT-only [0.85 (95%CI 0.81–0.90)]. In contrast, in EarlyR-High, the 5-year DRFS was higher (p = 0.019) in NACT + AHT [0.81 (95%CI 0.70–0.93)] as compared to AHT-only [0.60 (95%CI 0.51–0.71)]. ConclusionsHigh EarlyR is strongly associated with pCR in patients treated with neoadjuvant chemotherapy. EarlyR also predicts poor DRFS outcomes for patients in EarlyR-High not receiving NACT, and improved survival in NACT-treated EarlyR-High patients. EarlyR is not only a prognostic assay but also a predictive assay that identifies patients, who are also likely to respond to chemotherapy.

Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy.

BackgroundStromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined.ObjectiveThe predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice.Patients and MethodsA total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed.ResultsFirst, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p = 0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00–1.07, p = 0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12–0.52, p < 0.001) and multivariate analyses (OR 0.35, 95% CI 0.14–0.87, p = 0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88–0.95, p < 0.001; OS: HR 0.88, 95% CI 0.83–0.94, p < 0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90–0.97, p < 0.001; OS: HR 0.92, 95% CI 0.86–0.98, p = 0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91–14.95, p < 0.001; OS: HR 10.29, 95% CI 2.37–44.66, p = 0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65–9.12, p = 0.002; OS: HR 4.74, 95% CI 1.02–22.01, p = 0.047) indicated that patients with ≥ 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs.ConclusionsOur study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle biopsy specimens are significantly correlated with pCR and prognosis in HER2-positive breast cancers. A 20% threshold for sTILs may be a feasible diagnostic marker to predict pCR to NAC and prognosis in patients with HER2-positive breast cancers.

Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment.

.Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing -score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on -score normalization using only tissue oxygen saturation () measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue to surrounding tissue are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.