Histological features of breast cancer, highly sensitive to chemotherapy.

BACKGROUND: To establish tailor-made therapy for breast cancer, we investigated the possibility of predicting chemotherapy sensitive cases based on pre-therapeutic histological features. METHODS: A total of 87 breast cancer patients underwent neoadjuvant chemotherapy with a paclitaxel (80 mg/m(2)/q1w, 12 courses)or an epirubicin regimen (90 mg/m(2)/q3wks, 4 courses). We investigated the chemo-sensitivity of invasive ductal carcinoma, solid-tubular carcinoma consisting of highly malignant cancer cells with many mitoses. We refer to this type of carcinoma as " chemo-sensitive carcinoma " and compared the histological therapeutic effects of chemo-sensitive and chemo-insensitive carcinomas. RESULTS:1) Out of 87 patients, 20 cases (23%) showed the histological features of chemo-sensitive carcinomas on pre-therapeutic needle biopsy specimens. The remaining 67 cases (77%) were classified as chemo-insensitive carcinoma. 2) Histologically marked or complete response were observed in 50% (10/20) of chemo-sensitive carcinomas and 10% (7/67) of chemo-insensitive carcinomas (chi(2)=15.33, p=0.0001). Multivariate analysis of chemo-sensitive carcinoma, including HER2, hormone receptor and p53 status, revealed that chemo-sensitive carcinoma had a significant correlation with the histological therapeutic effects (p=0.01119). 3) Pathological complete response (pCR) was achieved in 35% (7/20) of chemo-sensitive carcinomas and 1.5% (1/67)of chemo-insensitive carcinomas (chi(2)=20.71, p<0.0001). Multivariate analysis revealed that chemo-sensitive carcinoma had a significant correlation with pCR (p=0.0091). CONCLUSION: The histological features of chemo-sensitive carcinoma were significant predictive factors for chemotherapeutic efficacy.     

Ki67 expression and localization of T cells after neoadjuvant therapies as reliable predictive markers in rectal cancer

Chemoradiotherapy (CRT) is the standard neoadjuvant therapy for locally advanced rectal cancer (RC). However, neoadjuvant chemotherapy (NAC) also shows favorable outcomes. Although the immunological environment of RC has been thoroughly discussed, the effect of NAC on it is less clear. Here, we investigated the immunological microenvironment, including T cell infiltration, activation, and topological distribution, of resected RC tissue after neoadjuvant therapies and evaluated the correlation between T cell subsets and patient prognosis. Rectal cancer patients (n = 188) were enrolled and categorized into 3 groups, namely CRT (n = 41), NAC (n = 46), and control (surgery alone; n = 101) groups. Characterization of residual carcinoma cells and T cell subsets in resected tissues was performed using multiplex fluorescence immunohistochemistry. The densities of total and activated (Ki67^high) T cells in tissues after NAC, but not CRT, were higher than in control. In both CRT and NAC groups, patients presenting with higher treatment effects showed aggressive infiltration of T cell subsets into carcinomas. Multivariate analyses of pathological and immunological features and prognosis revealed that carcinoma Ki67^highCD4⁺ T cells after CRT and stromal Ki67^highCD8⁺ T cells after NAC are important prognostic factors, respectively. Our results suggest that evaluation of T cell activation with Ki67 expression and its tumor localization can be used to determine the prognosis of advanced RC after neoadjuvant therapies.     

The Role of Immunohistochemistry in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: An Old Tool With an Enduring Prognostic Value

BackgroundTo assess the molecular subtypes determined by hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status and the role of proliferation measured by the Ki-67 marker as predictive and prognostic factors in breast cancer patients treated with neoadjuvant chemotherapy.MethodsA total of 127 breast cancer patients were treated with neoadjuvant chemotherapy every 2 weeks as part of 2 studies. Study A consisted of the administration of Adriamycin (40 mg/m²) on day 1 plus paclitaxel (150 mg/m²) and gemcitabine 2000 mg/m²) on day 2 for 6 cycles (n = 54). Study B consisted of the administration of epirubicin (90 mg/m²), cyclophosphamide (600 mg/m²) on day 1 for 3 cycles, followed by the administration of paclitaxel (150 mg/m²) and gemcitabine 2500 (mg/m²) on day 1 with or without trastuzumab according to HER2 status (n = 73). In study A, patients did not receive trastuzumab regardless of HER2 status. The molecular subtypes of the patients with breast cancer were classified as 49% HR⁺/HER2^?, 17.5% HR⁺/HER2⁺, 13.5% HR^?/HER2⁺, and 20% HR^?/HER2^?.ResultsPathologic complete response (pCR), defined as the absence of invasive cells in the breast and the lymph nodes, was achieved in 35 (28%) patients. The pCR rate was significantly different between the molecular subtypes of breast cancer, with 9% in HR⁺/HER2^?, 23% in HR⁺/HER2⁺, 50% in HR^?/HER2⁺, and 56% in HR^?/HER2^? tumors (P < .001). The pCR rate was significantly higher in tumors that had high Ki-67 (≥20%) expression and were HR^?. HER2⁺ was associated with a higher trend of pCR but did not reach statistical significance. The median follow-up was 81 months (r = 15-150 months). Patients who achieved a pCR had a significantly lower recurrence (P = .01) and higher overall survival (P = .02) compared with those who did not achieve pCR. A multivariate analysis revealed that pCR (hazard ratio 0.24 [95% CI, 0.07-0.7]; P = .019), the molecular subtype (hazard ratio 0.3 [95% CI, 0.1-0.8]; P = .02), and the Ki-67 index (hazard ratio 3.2 [95% CI, 1.4-7.1]; P = .004) were significant independent predictors of disease-free survival. Similar results were obtained for overall survival, in which the pCR rate (hazard ratio 0.119 [95% CI, 0.028-0.5]; P = .004), the molecular subtype (hazard ratio 0.17 [95% CI, 0.03-0.86]; P = .02), and the Ki-67 index (hazard ratio 3.6 [95% CI, 1.3-9.7]; P = .01) also displayed a significant influence on survival.ConclusionsMolecular subtypes and Ki-67 index were independent prognostic factors for disease-free survival and overall survival in breast cancer patients treated with neoadjuvant chemotherapy. A high rate of Ki-67 and HR^? expression were predictors of pCR.     

Tumour molecular subtyping according to hormone receptors and HER2 status defines different pathological complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

Purpose  To study the role of breast cancer molecular subtypes according to hormone receptors and HER2 status as a predictive factor for pathological complete response (pCR) to neoadjuvant chemotherapy. Patients and methods  Eligible patients received one of the two chemotherapy schedules every two weeks with prophylactic growth factor support; schedule A: epirubicin 90 mg/m²-cyclophosphamide 600 mg/m² d1 for 3 cycles followed by a second sequence with paclitaxel (P) 150 mg/m²-gemcitabine (G) 2500 mg/m² d1±trastuzumab (T) 2 mg/kg/week according to HER2 status (n=73); schedule B: adriamycin (40 mg/m²) d1 plus P (150 mg/m²)-G (2000 mg/m²) d2 for 6 cycles (n=54). Subsequently, patients underwent surgery, radiotherapy and/or adjuvant hormonal therapy according to standard practice. Results  A total of 127 patients were evaluated. Forty-three patients (33.9%) achieved a pCR (50% in patients with HER2+tumours treated with T). Patients treated with chemotherapy alone (n=107, 18 HER2+) had a pCR of 32% (p=0.068). The pCR rate for patients with triple negative (HR and HER2−) cancers was 58.3%, 39.5% for HER2+ and 5.4% for ER/PR+ and HER2− (p<0.001). No differences in disease-free survival (DFS) were noted as a function of pCR, HER2 and HR status or treatment received (±T). However, statistical differences in DFS were observed as a function of whether patients had + or − axillar lymph nodes. Patients with + lymph node disease did worse (3 years DFS of 53.7% vs. 81.5%, p=0.025). Breastconserving surgery was performed in 77 patients (60.6%). Conclusion  Tumour molecular subtyping defines different pCR to neoadjuvant chemotherapy (NC) but has no impact over DFS in patients with LABC. Although no significant correlation between HER2 status and trastuzumab therapy with pCR was found, probably due to the small number of patients, a favourable trend was observed in the group of HER2+ tumours treated with T.     

Efficacy of deescalated chemotherapy according to PAM50 subtypes,immune and proliferation genes in triple-negative early breast cancer: Primary translational analysis of the WSG-ADAPT-TN trial

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m² (plus carbo AUC2 or gem 1,000 mg/m² d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.     

Proliferation markers predictive of the pathological response and disease outcome of patients with breast carcinomas treated by anthracycline-based preoperative chemotherapy

The cell proliferation rate has been correlated to the response of breast carcinomas to preoperative chemotherapy (CT) and to disease outcome. However, this parameter is not yet used to select which tumours should be treated with preoperative CT. Furthermore, there is no consensus in the method used to evaluate cell proliferation. In poor prognosis breast carcinomas (PPBCs) treated by intensive preoperative CT, we compared the predictive value of S phase fraction (SPF), mitotic index (MI) and Ki67. We also evaluated the prognostic significance of the variation of the MI after CT. A series of 55 T2-T4N0N1M0 breast carcinomas were treated with 4 cycles of cyclophosphamide, 5-fluorouracil (5-FU) and doxorubicin. SPF was determined by flow cytometry on pre-therapeutic needle aspiration products. MI and Ki67 were evaluated on pre-therapeutic biopsy samples and on the tumours after CT. Fifteen patients (27%) had a pathological complete response (pCR), whereas 40 (73%) had residual disease. All three proliferative markers were found to have predictive value, but this value was higher for MI than for SPF (P = 0.04) and Ki67 (P = 0.03): the rate of pCR was 50% in cases with MI > 17/3.3 mm2, but was only 7% in cases with MI under this threshold (P = 0.0003). A significant decrease of MI (mean 10.97) was observed after CT (P = 0.001). Furthermore, we observed that even for patients with residual tumour, the variation of MI after CT was a prognostic parameter and overall survival. The sequential analysis of MI in breast cancers treated by preoperative CT thus provides a surrogate for predicting long-term outcome.     

Platelet/Lymphocyte Ratio Is Superior to Neutrophil/Lymphocyte Ratio as a Predictor of Chemotherapy Response and Disease-free Survival in Luminal B-like (HER2−) Breast Cancer

BackgroundThe neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been associated with the prognosis in breast cancer (BC). The relationship of the NLR and PLR with chemotherapy sensitivity and prognosis in luminal B-like (human epidermal growth factor receptor 2-negative [HER2⁻]) BC are not well studied.Patients and MethodsThe clinical data from 980 patients with luminal B-like (HER2⁻) BC from June 2012 to June 2016 were collected. The differences among the variables were calculated using the χ² test. The associations among the clinicopathologic factors, pretreatment NLR, pretreatment PLR, and disease-free survival (DFS) were analyzed using Kaplan-Meier curves and Cox analyses.ResultsThe median follow-up was 37 months (range, 5-77 months). For the 480 patients who had received neoadjuvant chemotherapy, low pretreatment PLR values were associated with higher pathologic complete response (pCR) rates compared with the high PLR group (15.8% for low vs. 9.2% for high PLR group; P = .027). Multivariate analyses showed that larger tumors, a greater number of lymph nodes involved, a high Ki-67 score, and a high PLR were independent prognostic factors of worse outcomes for the patients with luminal B-like (HER2⁻) BC. The risk of metastasis and/or recurrence was greater for the high PLR group than for the low PLR group (hazard ratio, 1.576; 95% confidence interval, 1.039-2.390; P = .032). The pretreatment NLR showed no such associations among this cohort of patients.ConclusionsThe results of the present study have shown that the pretreatment PLR is superior to the NLR as a predictor of pCR and DFS outcomes in patients with luminal B-like (HER2⁻) BC. A low pretreatment PLR was associated with higher pCR rates after neoadjuvant chemotherapy and was an independent predictive factor for better DFS outcomes among patients with luminal B-like (HER2⁻) BC.     

Imaging and Clinicopathologic Features Associated With Pathologic Complete Response in HER2-positive Breast Cancer Receiving Neoadjuvant Chemotherapy With Dual HER2 Blockade

BackgroundIn human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer, the incorporation of a dual HER2 blockade into neoadjuvant chemotherapy (NAC) has been shown to induce a higher rate of pathologic complete response (pCR). The purpose of this study was to investigate whether pretreatment imaging and clinicopathologic features show any association with pCR in HER2⁺ breast cancer receiving NAC plus dual blockade.Materials and MethodsThis retrospective study evaluated 94 consecutive patients (mean age, 49.8 ± 9.9 years) with HER2⁺ breast cancer who underwent NAC plus dual blockade with trastuzumab and pertuzumab between April 2016 and June 2018. All patients underwent mammography, ultrasound, and magnetic resonance imaging prior to NAC. Clinicopathologic and imaging features acquired before NAC were evaluated for their ability to predict the pathologic response after surgery. Multivariate analysis was used to identify independent predictors of pCR.ResultsFifty patients (53.2%) showed pCR and 44 (46.8%) did not. According to a univariate analysis, fine pleomorphic/fine linear or linear-branching calcification morphology on mammography, parallel orientation on ultrasound, intratumoral high signal intensity on T2-weighted magnetic resonance imaging, progesterone receptor negativity, and high levels of tumor-infiltrating lymphocytes were associated with pCR. On multivariate analysis, fine pleomorphic/fine linear or linear-branching calcification morphology on mammography (odds ratio [OR], 7.23), progesterone receptor negativity (OR, 6.76), and a high tumor-infiltrating lymphocyte level (OR, 5.92) remained significant independent factors associated with pCR.ConclusionSeveral pretreatment imaging and clinicopathologic features were shown to be independent variables predicting pCR in patients with HER2⁺ breast cancer receiving NAC with dual blockade.     

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.     

乳腺癌临床病理指标以及分子分型对TEC新辅助化疗病理完全缓解的预测价值

目的  本研究旨在探讨乳腺癌临床病理指标以及乳腺癌分子分型对多西他赛联合表柔比星、环磷酰胺（TEC）的 新辅助化疗后病理完全缓解率（pathological complete response pCR）的预测价值。方法   对 214例经4周期TEC新辅助化疗的乳腺癌患者的临床病理资料进行回顾性分析;免疫组织化学检测经核心针穿刺 的癌组织雌激素受体（ER）、孕激素受体（PR）、人类表皮生长因子受体-2（HER2）、Ki67、p53表达情况,原位基 因免疫荧光杂交（FISH）检测HER2有无过表达;根据ER、PR、HER2、Ki67的表达情况将乳腺癌分为4种分子分型： LuminalA、 LuminalB、HER2过表达型和三阴性乳腺癌。分析不同的临床病理指标、不同分子分型与pCR的相关性。结果  4周期TEC新辅助化疗后pCR率为14.0%（30/214）;单因素分析：ER、PR、Ki67、乳腺癌分子分型与pCR均具有显 著相关性（P＜0.05）;乳腺癌分子分型各组间显示pCR率不同：LuminalA＜LuminalB＜HER2过表达型＜三阴性乳腺癌 ;多因素分析：与pCR具有显著相关性的分类变量为ER（OR=0.311,95%CI：0.136～0.712;P=0.006）和Ki67 （OR=2.788,95%CI：1.061～7.327;P=0.038）。结论  ER、PR、Ki67以及乳腺癌分子分型可能是TEC新辅助化疗后乳腺癌pCR的预测指标。     

Dynamic breast magnetic resonance imaging: pretreatment prediction of tumor response to neoadjuvant chemotherapy

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may have the potential of predicting response to neoadjuvant chemotherapy for patients with breast cancer. However, most of these studies focused on evaluating hot-spot characteristics. To thoroughly reflect tumor status, the cold spot and heterogeneity characteristics should also be evaluated.Patients and MethodsDCE-MRIs from 60 patients newly diagnosed with primary invasive breast cancer were reviewed. Kinetic parameters (including cold spot, hot spot, and heterogeneity parameters) derived from DCE-MRI data were used to describe cold spot, hot spot, and heterogeneity features. Patients with a pathologic complete response (pCR) or a ductal carcinoma in situ with microinvasion after chemotherapy were categorized into the pCR group. Pretreatment kinetic parameters in the pCR and non-pCR groups were compared by using univariate tests. Binary logistic regression analysis was used to identify the independent predictors for pCR. The best cutoff value of the independent predictor at pretreatment, with which to differentiate between patients who had a pCR and a non-pCR, was calculated by using receiver operating characteristic curve analysis.ResultsAfter chemotherapy, 10 (16.7%) patients were categorized into the pCR group and 50 (83.3%) into non-pCR group. Multivariate analysis showed that pretreatment washout slope at a cold spot (washout^C) was the only significant and independent predictor of pCR (β = 26.128; P = .005). The best pretreatment washout^C cutoff value with which to differentiate between patients who had pCR and those with non-pCR was 0.0277, which yielded a sensitivity of 80.0% (95% CI, 44.4%-97.5%) and a specificity of 74.0% (95% CI, 59.7%-85.4%).ConclusionWashout^C may be used as a predictor for pCR in patients with breast cancer who undergo neoadjuvant chemotherapy.     

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study

BackgroundIn human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole.Patients and methodsPerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon’s design, to reject the null hypothesis, at least 8/43 pCR had to be documented.ResultsSixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042).ConclusionsThe primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared.EUDRACT number2013-002662-40ClinicalTrials.gov IdentifierNCT02411344     

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer

IntroductionNeoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.MethodsWe conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m² IV weekly ×12 followed by doxorubicin 24 mg/m² IV weekly + cyclophosphamide 60 mg/m² PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade).ResultsSeventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER⁺ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue.ConclusionsNeoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.     

Surrogate end-points for overall survival in 22 neoadjuvant trials of gastro-oesophageal cancers

BackgroundThe surrogacy between disease-free survival (DFS) and overall survival (OS) has been evaluated in patients with gastric cancer who received adjuvant chemotherapy. Similar analyses in patients who have undergone neoadjuvant chemoradiotherapy (CTRT) or chemotherapy (CT) for gastro-oesophageal (GE) cancer have not yet been performed.MethodsWe evaluated the correlation between DFS and pathologic complete response (pCR) with OS in patients with GE carcinomas enrolled in randomised studies. A weighted linear regression analysis was used to evaluate surrogacy. Correlations were evaluated by squared correlation R². Surrogacy of DFS and pCR with OS was assessed through the correlation between end-points and OS (individual-level surrogacy), and between the treatment effects on the end-points (trial-level surrogacy). Correlations were weighted by the number of patients in the intent-to-treat population.ResultsTwenty-two trials were included for a total of 4749 patients that received CTRT or CT for gastric or oesophageal cancers. Treatment effect on surrogates did not correlate with treatment effect on OS (R² = 0.27, and R² = 0.17, for DFS and pCR) at the trial level. In subgroup analysis surrogacy of DFS did not vary according to histology or treatment modality but was good in gastric cancer and poor in oesophageal cancers.ConclusionsDFS and pCR did not correlate with OS, and should not be used as surrogate end-points in patients with GE cancer who have undergone neoadjuvant therapy. OS should still represent the primary end-point to compare treatments in future randomised clinical trials.     

Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer

Purpose

Recently, Ki67 index (cell proliferation marker) has been attracting a considerable attention as a prognostic factor in breast cancer but the prognostic significance of Ki67 after neoadjuvant chemotherapy (NAC) has rarely been examined.

Experimental design

Primary breast cancer patients (n = 102) treated with NAC (sequential paclitaxel 12 cycles (q1w) and 5-FU/epirubicin/cyclophosphamide 4 cycles (q3w)) were recruited in the study. Ki67, estrogen receptor (ER) and progesterone receptor (PR) and breast cancer resistant protein (BCRP) and P-glycoprotein were determined by immunohistochemistry and HER2 was determined by FISH in tumor tissues obtained before and after NAC, and their association with patient prognosis (relapse-free survival) was examined.

Results

Of the 102 patients, pCR was achieved in 30 (29.4%). In the 72 non-pCR patients, Ki67 index significantly (P < 0.001) decreased after NAC. Ki67 index after NAC, but not Ki67 index before NAC, was significantly associated with a patient prognosis (P = 0.022). Multivariate analysis has shown that Ki67 index after NAC is a marginally significant (P = 0.05) prognostic factor and that other biomarkers including ER, PR, BCRP, and P-glycoprotein before and after NAC are not significant.

Conclusions

Ki67 after NAC, but not before NAC, is prognostic in breast cancer patients, and might be clinically useful in the prognosis prediction of patients who do not achieve pCR after NAC. On the other hand, BCRP and P-glycoprotein before and after NAC are unlikely to be useful as prognostic factors in these patients.     

Randomized phase II study of primary systemic chemotherapy and trastuzumab for operable HER2 positive breast cancer

BackgroundIn primary systemic therapy in patients with human epidermal growth factor receptor 2 positive (HER2⁺) breast cancer, improvements in pathologic complete response (pCR) rate have been achieved by administering trastuzumab.Patients and MethodsPatients with stage II or IIIA HER2⁺ operable breast cancer were randomly assigned to receive four 3-weekly cycles of FEC (5-fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²) followed by 4 cycles of 3-weekly trastuzumab (8 mg/kg week 1 and then 6 mg/kg) with either 12 weekly doses of paclitaxel 80 mg/m² (FEC-PH) or 4 cycles of 3-weekly docetaxel 75 mg/m² (FEC-DH).ResultsBetween March 2007 and June 2008, 102 patients were enrolled. Forty-nine patients receiving FEC-PH and 47 receiving FEC-DH were assessable for efficacy and safety. Eighty-four patients completed treatment and underwent surgery. There was no significant difference in the pCR rate between the 2 groups (46.9% [95% CI, 33.7%-60.6%] with FEC-PH vs. 42.6% [95% CI, 29.5%-56.8%] with FEC-DH; P = .67). Analysis by hormone receptor (HR) status showed pCR rates of 54.2% (32/59) in HR^? tumors and 29.7% (11/37) in HR⁺ tumors (P = .02). Among HR^? tumors, the pCR rates were 65.4% and 45.5% in patients treated with FEC-PH and FEC-DH, respectively (P = .13).ConclusionsThere was no significant difference in pCR rate between FEC-PH and FEC-DH. Both regimens achieved higher pCR rates in HR^? than HR⁺ breast cancer, and there was a trend toward higher pCR in HR^? tumors with FEC-PH compared with FEC-DH. Further investigation is warranted to explore the relationship between efficacy and HR status.     

Feasibility,Safety, and Preliminary Efficacy of Exercise During and After Neoadjuvant Rectal Cancer Treatment: A Phase II Randomized Controlled Trial

BackgroundNeoadjuvant chemoradiation (NACRT) improves outcomes for patients with rectal cancer; however, there are dose-limiting toxicities and only a 15% to 27% pathologic complete response (pCR) rate. Exercise may help manage toxicities and improve treatment response, but feasibility and early efficacy have not been established. EXERT was a phase II trial designed to establish the feasibility and safety of exercise and provide the first evidence of efficacy.Materials and MethodsPatients with rectal cancer scheduled to receive NACRT were randomly assigned to usual care (n = 18) or exercise (n = 18) involving supervised exercise during NACRT and unsupervised exercise after NACRT. The primary outcome was cardiorespiratory fitness (VO₂ peak). Clinical outcomes included treatment toxicities, treatment completion, and treatment response.ResultsMedian attendance at supervised exercise sessions during NACRT was 82%, and median self-reported exercise after NACRT was 90 min/wk. From baseline to post-NACRT, VO₂ peak increased by 0.4 mL·kg⁻¹·min⁻¹ in the exercise group and decreased by 0.8 mL·kg⁻¹·min⁻¹ in the usual care group (P = .47). There were no significant differences between groups for grade 3/4 toxicities or treatment completion. Of 18 patients in the exercise group, 10 (56%) achieved pCR/near pCR compared with 3 of 17 (18%) in the usual care group (P = .020).ConclusionExercise during and after NACRT is feasible for many patients with rectal cancer and may improve pCR despite limited fitness improvements. Larger trials are warranted to confirm if exercise is an effective intervention for improving treatment outcomes in this clinical setting.     

Assessment of different criteria for the pathological complete response (pCR) to primary chemotherapy in breast cancer: standardization is needed

Purpose Evaluation of the safety and efficacy of a combination of docetaxel and doxorubicin in breast cancer patients. Evaluation and comparison of the pathological complete response (pCR) to this regimen according to various definitions in different clinical trials. Utilize the data to propose standardization of definitions. Patients and Methods Between 1998 and 2001, 141 patients with stage II (tumor size >3.0 cm) or III breast cancer were treated with doxorubicin 50 mg/m² followed by docetaxel 60 mg/m² (AT) on day 1. A total of 4 courses of AT were administered as primary chemotherapy with intervals of 3 weeks. Additionally, 2 cycles of the same regimen were administered after surgery when clinical CR or PR was achieved; otherwise, 4 cycles of CMF were added postoperatively. Results 141 patients were enrolled in this trial. A clinical response rate was 86%. Seven patients (5%) achieved pCR according to the Japanese Breast Cancer Society classification, 14 patients (10%) fulfilled the University of Texas M.D. Anderson Cancer Center trial’s pCR criteria, and 19 patients (14%) met the NSABP trial pCR definition. NCI CTC version 2 grade 3/4 toxicities included leucopenia (26%), neutropenia (85%) and febrile neutropenia (12%). Conclusion Primary chemotherapy with AT induced modest tumor responses with tolerable toxicity. Differences in the definition of pCR among clinical trials caused substantial confusion in interpreting the trial results. Therefore, standardization of the pCR definition after primary chemotherapy is needed.     

Nomogram predicting response after chemoradiotherapy in rectal cancer using sequential PETCT imaging: A multicentric prospective study with external validation

PurposeTo develop and externally validate a predictive model for pathologic complete response (pCR) for locally advanced rectal cancer (LARC) based on clinical features and early sequential ¹⁸F-FDG PETCT imaging.Materials and methodsProspective data (i.a. THUNDER trial) were used to train (N = 112, MAASTRO Clinic) and validate (N = 78, Università Cattolica del S. Cuore) the model for pCR (ypT0N0). All patients received long-course chemoradiotherapy (CRT) and surgery. Clinical parameters were age, gender, clinical tumour (cT) stage and clinical nodal (cN) stage. PET parameters were SUV_max, SUV_mean, metabolic tumour volume (MTV) and maximal tumour diameter, for which response indices between pre-treatment and intermediate scan were calculated. Using multivariate logistic regression, three probability groups for pCR were defined.ResultsThe pCR rates were 21.4% (training) and 23.1% (validation). The selected predictive features for pCR were cT-stage, cN-stage, response index of SUV_mean and maximal tumour diameter during treatment. The models’ performances (AUC) were 0.78 (training) and 0.70 (validation). The high probability group for pCR resulted in 100% correct predictions for training and 67% for validation. The model is available on the website www.predictcancer.org.ConclusionsThe developed predictive model for pCR is accurate and externally validated. This model may assist in treatment decisions during CRT to select complete responders for a wait-and-see policy, good responders for extra RT boost and bad responders for additional chemotherapy.     

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil–epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m² on day 1; capecitabine: 1,650 mg/m² on days 1–14 every 3 weeks) or docetaxel alone (75 mg/m² on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m² on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10–20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014–1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.