The impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a National Cancer Database (NCDB) analysis

BackgroundFollowing neoadjuvant chemotherapy (NAC), the optimal strategies for postmastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after breast-conserving surgery (BCS) are controversial. In this analysis, we evaluate the impact of these radiotherapy (RT) approaches for women with clinically node-positive breast cancer treated with NAC in the National Cancer Database (NCDB).Patients and methodsWomen with cT1–3 cN1 M0 breast cancer treated with NAC were divided into four cohorts by surgery [Mastectomy (Mast) versus BCS] and post-chemotherapy pathologic nodal status (ypN0 versus ypN+). Overall survival (OS) was estimated using the Kaplan–Meier method and RT approaches were analyzed using the log-rank test, multivariate Cox models, and propensity score-matched analyses.ResultsFrom 2003 to 2011, 15 315 cases were identified including 3040 Mast-ypN0, 7243 Mast-ypN+, 2070 BCS-ypN0, and 2962 BCS-ypN+ patients. On univariate analysis, PMRT was associated with improved OS for both Mast-ypN0 (P = 0.019) and Mast-ypN+ (P < 0.001) patients. On multivariate analyses adjusted for factors including age, comorbidity score, cT stage, in-breast pathologic complete response, axillary surgery, ypN stage, estrogen receptor status and hormone therapy, PMRT remained independently associated with improved OS among Mast-ypN0 [hazard ratio (HR) = 0.729, 95% confidence interval (CI) 0.566–0.939, P = 0.015] and Mast-ypN+ patients (HR = 0.772, 95% CI 0.689–0.866, P < 0.001). No differences in OS were observed with the addition of RNI to breast RT for BCS-ypN0 or BCS-ypN+ patients. Propensity score-matched analyses demonstrated identical patterns of significance. On subset analysis, OS was improved with PMRT in each pathologic nodal subgroup (ypN0, ypN1, and ypN2-3) (all P < 0.05).ConclusionsIn the largest reported analysis of RT for cN1 patients treated with NAC, PMRT was associated with improved OS for all pathologic nodal subgroups. No OS differences were observed with the addition of RNI to breast RT.     

Regional Nodal Irradiation for Clinically Node-Positive Breast Cancer Patients With Pathologic Negative Nodes After Neoadjuvant Chemotherapy

IntroductionNeoadjuvant chemotherapy (NAC) is increasingly used for operable breast cancer (BC). Appropriate radiation therapy (RT) fields (ie, whole breast [WB] ± regional nodal irradiation [RNI]) in patients who were clinically node positive (cN1) but convert to pathologically node negative (ypN0) after NAC are unknown and the subject of the accruing NSABP B-51 trial. We sought to compare outcomes between WB RT with or without RNI following breast conservation and sentinel lymph node biopsy (SLNB) alone in cN1, ypN0 women following NAC.Patients and MethodsWe identified all BC patients with cN1, ypN0 who underwent NAC followed by lumpectomy and SLNB between 2006 and 2015 in the National Cancer Database. RNI utilization was evaluated using Cochran-Armitage test. Overall survival between WB RT alone versus WB + RNI was compared using Kaplan-Meier with and without propensity score-based weighted adjustment and multivariable (MVA) Cox proportional hazards.ResultsFrom 2006 to 2015, RNI use increased from 48.13% to 62.13% (Pfor trend <.001). The 10-year survival for WB alone versus WB + RNI was 83.6% and 79.5%, respectively (P= .14). On MVA analysis, the addition of RNI compared to WB alone was not associated with a survival benefit (WB vs. WB + RNI: hazard ratio 0.80, 95% confidence interval, 0.58-1.11, P= .19). Results were unchanged after propensity score-based adjustment.ConclusionFor women with cN1 BC who convert to ypN0 following NAC and breast conserving surgery with SLNB alone, more extensive RNI may not provide a long-term survival benefit. Prospective validation via the NSABP B-51 trial will be essential.     

Locoregional Recurrence and Survival Outcomes in Breast Cancer Treated With Modern Neoadjuvant Chemotherapy: A Contemporary Population-based Analysis

BackgroundData guiding radiotherapy (RT) decisions after neoadjuvant chemotherapy (NAC) is largely retrospective, based on older treatment approaches without molecular subtype information. This study evaluated outcomes in breast cancer patients treated with modern NAC by molecular subtype and locoregional treatment.Materials and MethodsThere were 949 patients diagnosed between 2005 and 2016 treated with NAC followed by surgery ± locoregional radiotherapy (LRRT). Outcomes were 7-year locoregional relapse-free survival (LRRFS), breast cancer-specific survival (BCSS), and overall survival (OS).ResultsMedian follow-up was 6.5 years, 92% had cT2-4 and 72% cN1-3 disease. Subtypes were: 21% Luminal A, 18% Luminal B, 35% Her2+, and 21% triple-negative breast cancer (TNBC). Combined taxane and anthracycline-based NAC was used in 91.7% of cases. All patients with Her2+ disease received anti-Her2 therapy. After NAC, the majority (84.9%) underwent mastectomy, and received LRRT (86.1%). Only 11% had mastectomy without RT. Pathologic complete response (pCR) rates were 2.5% for Luminal A, 14.4% Luminal B, 27% TNBC, and 35.1% Her2+. Overall, adjuvant LRRT was associated with improved outcomes but was most significant for improved LRRFS in TNBC (92.5% vs. 68.5%, P < .001; Her2+ 95.4% vs. 93.6%, P = .81; Luminal A 97.4% vs. 100%, P = .49; Luminal B 89.7% vs. 100%, P = .17). On multivariable analysis, factors associated with reduced LRRFS were grade 3 histology (HR 4.96, P = .009) and no pCR (HR 7.0, P = .0008). Predictors of lower BCSS and OS were age >50, grade 3, cT3-4, lack of pCR, LRRT omission, and TNBC and Her2+ subtypes.ConclusionIn this analysis of patients treated with modern NAC, pCR rates varied by molecular subtype. Patients who did not receive LRRT, particularly those with TNBC, had lower survival compared to those treated with LRRT. These findings support the need for prospective studies to evaluate the safety of de-escalating RT after NAC.     

Neoadjuvant Chemotherapy in Elderly Patients With Upper Tract Urothelial Cancer: Oncologic Outcomes From a Multicenter Study

IntroductionAlthough upper tract urothelial carcinoma (UTUC) is more common in the elderly, outcomes of neoadjuvant chemotherapy (NAC) in this population have never been explored. The objective of the study was to assess the impact of NAC on pathologic response and oncological outcomes stratified by age.Patients and MethodsThis multicenter study included 164 patients treated with NAC and radical nephroureterectomy (RNU) for clinically non-metastatic, high-risk UTUC. The cohort was stratified into two groups according to median age. Patients received either cisplatin-based or non-cisplatin-based chemotherapies. Pathologic responses were defined as pathologic objective response (pOR; ≤ ypT1N0) and pathologic complete response (pCR; ypT0N0). Univariable and multivariable logistic and Cox regression analyses were performed to identify predictors for pathologic response and survival outcomes.ResultsThe cohorts’ median age was 68 years with the elderly group (> 68 years) comprising 74 patients. Neoadjuvant chemotherapy included methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) in 66 (40%), gemcitabine cisplatin (GC) in 66 (40%) and non-cisplatin chemotherapy in 32 patients (20%). Younger patients received more often MVAC (50% vs. 28%) while elderly received more GC (34% vs. 47%) or non-cisplatin chemotherapy (16% vs. 24%) (P = .02). Overall, pOR and pCR were similar across age groups (52% vs. 47%; P = .5 and 10% vs. 8%; P = .7). While GC and non-cisplatin chemotherapy showed a lower pCR of 5% and 3%, respectively, MVAC revealed a pCR of 17% (P = .03) and was independently associated with a higher pCR (OR 4.31; P = .03). Kaplan-Meier analysis showed no difference in recurrence-free and cancer-specific survival, whereas a lower rate was seen in overall survival for the elderly.ConclusionElderly patients with high-risk UTUC eligible for cisplatin-based NAC prior to RNU may benefit from this multimodal therapy equally as their younger counterparts. Cisplatin-ineligible patients undergoing non-cisplatin-based NAC appeared to have lower response rates and should be considered for immediate RNU.     

Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)

BackgroundWe evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC).Patients and methodsPatients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m²; q3w) followed by four cycles docetaxel (100 mg/m²; q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy.ResultsTNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23–2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24–4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14–2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis.ConclusionsThe addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.     

Favorable outcome with sentinel lymph node biopsy alone after neoadjuvant chemotherapy in clinically node positive breast cancer at diagnosis: Turkish Multicentric NEOSENTI-TURK MF-18-02-study

PurposeFactors affecting local outcome were evaluated in patients with clinically node-positive (cN+) breast cancer at diagnosis, who underwent sentinel lymph node biopsy (SLNB) alone after neoadjuvant chemotherapy (NAC).MethodsBetween 2004 and 2018, 303 cytopathology-proven cN (+) patients in a multicentric registry, who received NAC and underwent SLNB alone were analysed. All patients had regional nodal irradiation.ResultsMedian age was 46 (23–70). Of those, 211 patients had ypN0 disease (69.6%), whereas 92 patients had ypN (+) disease including 19 (20.6%) isolated tumor cells (ITC), 33 micrometastases (35.9%) and 40 macrometastases (43.5%). At a median follow-up of 36 months (24–172), one patient (0.3%) with macrometastatic SLN was found to have locoregional recurrence as chest wall and supraclavicular LN metastases at the 60th month. Five-year disease-free survival (DFS) and disease specific survival (DSS) rates were 87% and 95%, respectively. Patients with cT3/4 (HR = 2.41, 95% CI; 1.14–5.07), non-luminal molecular pathology (HR = 2.60, 95% CI, 1.16–5.82), and non-pCR in the breast (HR = 2.11, 95% CI, 0.89–5.01) were found to have an increased HR compared to others in 5-year DFS. However, no difference could be found between ypN0 and ypN ITC and micrometastasis (HR = 1.23, 95% CI, 0.44–3.47), whereas there was a slight increase in HR of patients with ypN macrometastasis versus ypN0 (HR = 1.91, 95% CI, 0.63–5.79).ConclusionALND could be avoided in meticulously selected cN (+) patients who underwent SLNB after NAC having breast and/or nodal pCR, cT1-2, or low volume residual nodal disease with luminal pathology, as long as axillary radiotherapy is provided.     

Neoadjuvant Chemotherapy for Metaplastic Breast Cancer: Response Rates,Management, and Outcomes

IntroductionNeoadjuvant chemotherapy (NAC) for breast cance has not been well studied for metaplastic breast cancer (MBC), a rare but aggressive type of breast cancer.Materials and MethodsThe National Cancer Database was queried (2004-2017) for females with cM0 MBC who received NAC and definitive surgery with a pathologic staging record. Statistics included Kaplan-Meier overall survival (OS) analysis, multivariable logistic regression, and Cox proportional hazards modeling.ResultsOf 903 MBC patients, 88 (9.8%) experienced a pathologic complete response (pCR). The vast majority of ypT0 cases were initially cT1-2. On multivariable logistic regression, cT1 disease was a single factor that was associated with pCR. The majority of patients with MBC undergoing pCR still underwent mastectomy (62.5%) and sentinel node biopsy (67.1%). Axillary dissection was more common in non-pCR cases (49.3% vs. 29.6%, P = .001). The 5 year OS difference amongst MBC patients between pCR vs. RCB1-3 was significant (93 vs. 63%, P < .001). There was no difference observed between MpBC with pCR and non-MpBC invasive ductal carcinoma (IDC) with pCR (93 vs. 93%), with pCR (P > .05 for all molecular subtypes).ConclusionThis study confirms that response rates of MBC to NAC are low, with pCR being relatively infrequent. However, early-stage MBC may be more likely to achieve pCR. These findings combined with emerging research on identifying favorable histopathologic subtypes of MBC may better elucidate subsets with higher proclivity for pCR, especially because these patients achieve satisfactory survival, comparable to that of IDC with pCR.     

The Prognostic Value of Tumor Regression Grades Combined With TNM Classification in Patients With Muscle-Invasive Bladder Cancer Who Underwent Neoadjuvant Chemotherapy Followed by Radical Cystectomy

IntroductionTumor regression grades (TRGs) quantify the pathologic response to neoadjuvant chemotherapy (NAC). The aim of the study was to investigate the prognostic value of TRGs in combination with the TNM classification in an independent cohort of patients with muscle-invasive bladder cancer (MIBC) treated with NAC followed by radical cystectomy (RC) in a retrospective setting.Patients and MethodsPatients treated with a complete course of NAC followed by RC for MIBC between December 2012 and December 2017 were enrolled in the study. TRGs were determined in RC specimens. Data were collected preoperatively, and the follow-up was continued up to August 2018. Kaplan-Meier curves and the Cox proportional hazards model were used to compare survival probabilities between major responders (no MIBC, < ypT2 and ypN0), partial responders (≥ ypT2 or ypN+ and TRG2), and non-responders (≥ ypT2 or ypN+ and TRG3).ResultsA group of 70 patients with a median age of 64 years (interquartile range, 58-67 years) was analyzed. There were 36 major responders, 21 partial responders, and 13 non-responders. In comparison with a major response, a partial response was associated with a hazard ratio of 9.44 (95% confidence interval, 1.10-80.89; P = .04) and non- responders showed a hazard ratio of 17.85 (95% confidence interval, 2.18-145.85; P = .007) for death.ConclusionsThe study confirms the prognostic value of the pathologic response to NAC. Determination of TRGs is straightforward, provides valuable information, and could be easily included in the standard pathologic examination of RC surgical specimen. Prospective studies are needed to establish the role of TRG in routine clinical practice.     

Characterization of Weakly Hormone Receptor (HR)-Positive,HER2-Negative Breast Cancer and Current Treatment Strategies

BackgroundHormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status is critical for determining management of breast cancer. Previous reports of small cohorts with weak HR-positive (HR+)/HER2-negative (HER2-) disease showed similar rates of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) as triple negative breast cancer (TNBC). This study aims to further characterize this group, focusing on pCR rates following NAC.Patients and MethodsPatients with stage I-III, HR+/HER2- breast cancer were identified using the University of Wisconsin Hospital Cancer Registry. Medical records were reviewed for demographics, tumor characteristics with quantification level of estrogen and progesterone receptor (≤33%), treatment, and follow-up data.ResultsData was reviewed from 2,900 patients and a total of 64 patients met inclusion criteria. Eighty percent received chemotherapy, about half with NAC (n = 30, 48%). Of 28 patients who received NAC followed by breast and axillary surgery, 12 (43%; 95% CI 25%-63%) had pCR (ypT0/Tis/ypN0). Of the 11 patients who had biopsyproven nodal disease at diagnosis and NAC followed by axillary surgery, 7 (64%, 95% CI 31%-89%) patients had pCR at the axilla. Only one patient with pCR developed recurrent disease. For those that recurred, median time to recurrence was 13.6 (5.6-48.7) months.ConclusionsBreast cancers that are HER2- and weakly HR+ treated with NAC demonstrated pCR rate more similar to TNBC than breast cancers that are strong HR+. Neoadjuvant approaches may improve pCR rates, which provides important prognostic information. Clinical trials should be developed to focus on this unique patient cohort.     

Randomised,open-label,phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE)

BackgroundThe GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)–negative breast cancer (BC) treated with either cabazitaxel or paclitaxel.MethodsGENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter.ResultsOverall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p < 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively.ConclusionsThe GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms.Clinical trials registrationClinicalTrials.gov NCT01779479.     

Usefulness of Restaging Pelvis Magnetic Resonance Imaging After Neoadjuvant Concurrent Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

IntroductionIn patients with locally advanced rectal cancer, restaging pelvis magnetic resonance imaging (MRI) after neoadjuvant concurrent chemoradiotherapy is recommended despite its limited accuracy in predicting pathologic T (ypT) and N (ypN) stage. Neoadjuvant rectal (NAR) score is a novel short-term surrogate endpoint for disease-free survival (DFS) and overall survival (OS). We tested the agreement between restaging MRI T (yT) and N (yN) with ypT and ypN stages, respectively, and explored the prognostic significance of restaging MRI NAR (mNAR) score.Patients and MethodsBetween 2014 and 2018, 43 patients with locally advanced rectal cancer completed neoadjuvant concurrent chemoradiotherapy, had a restaging MRI, and underwent surgery. Weighted kappa was used to test the agreement between yT and yN with ypT and ypN, respectively. A kappa value of less than 0.5 was deemed unacceptable. Paired t test was used to compare NAR and mNAR mean scores. Survival was estimated by Kaplan-Meier curves.ResultsRestaging MRI could not predict ypT stage (slight agreement, κ = 0.111) or ypN stage (fair agreement, κ = 0.278). The mean mNAR score was higher than the mean NAR score (20 vs. 16, P = .0079). The median DFS for patients with low-intermediate NAR and high NAR was not reached vs. 30 months (P = .0063). The median OS for patients with low-intermediate NAR and high NAR was not reached vs. 40 months (P = .0056). There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores (not reached in both groups, P = .058) compared to patients with high mNAR scores (not reached in both groups, P = .15).ConclusionRestaging MRI could not predict ypT and ypN stage. The mean mNAR score was higher than the mean NAR score. There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores compared to patients with high mNAR scores.     

Poorer Oncologic Outcome of Good Responders to PCRT With Remnant Lymph Nodes Defies the Oncologic Paradox in Patients With Rectal Cancer

IntroductionWe evaluated the oncologic outcome of (y)pT0-2N+ rectal cancer and investigated the impact of metastatic lymph nodes (LNs) on oncologic outcome in the setting of preoperative chemoradiotherapy (PCRT).Materials and MethodsThe records of 1403 patients who underwent surgery for rectal cancer between January 2005 and December 2012 were analyzed. The patients were categorized according to the pathologic stage, including 728 patients with ypT0-2 and 675 with ypT3-4 disease. The oncologic outcomes in terms of the 5-year recurrence-free survival (RFS) and overall survival (OS) were analyzed.ResultsMetastatic LNs were observed in 11.5% (n = 84) of patients with ypT0-2 and 42.9% (n = 290) of patients with ypT3-4 disease. The RFS and OS were stratified according to ypT and ypN stage as ypT0-2N0, T0-2N+, T3-4N0, and T3-4N+. The ypT0-2N+ group had slightly lower RFS and OS than those in the ypT3-4N0 group. LN metastasis was significantly associated with RFS in both ypT0-2 and ypT3-4 disease, with a stronger association for ypT0-2 disease (hazard ratio, 3.473, 95% confidence interval, 2.058-5.261; P < .001 for ypT0-2 and hazard ratio, 2.038; 95% confidence interval, 1.601-2.684; P < .001 for ypT3-4, respectively).ConclusionThe oncologic outcomes of ypT0-2N+ disease were not favorable compared with those of ypT3-4N0 disease. These outcomes dispute the survival paradox traditionally believed for non-PCRT-treated patients with rectal cancer, and highlight the underestimated significance of post-PCRT nodal involvement. The prognostic importance of metastatic LNs should be considered when deciding the surgical strategy after PCRT. Further studies including larger numbers of patients with sufficient follow-up are needed to verify the oncologic impact of metastatic LNs within tumors contained within the bowel wall after PCRT.     

Factors Associated With Surgical Modality Following Neoadjuvant Chemotherapy in Patients with Breast Cancer

BackgroundThe breast-conserving surgery (BCS) rate for patients with breast cancer in China is much lower than that in Europe and the United States. This study aimed to identify factors affecting the choice of surgical modality following neoadjuvant chemotherapy (NAC) in patients with breast cancer in northwest China.Patients and MethodsPatients who underwent mastectomy or BCS after NAC for invasive breast cancer from January 2013 to December 2017 were enrolled in the study. Single-factor and multivariate logistic regression analyses were applied to identify the association between the type of surgery and demographic characteristics or clinical pathological factors of patients.ResultsThis study enrolled 916 patients. Among them, 191 patients (20.9%) and 725 patients (79.1%) underwent BCS and mastectomy, respectively. Patients with high education were less likely to undergo mastectomy compared with patients with less education (P < .001; odds ratio [OR] = 0.50; 95% confidence interval [CI], 0.35-0.71). Patients with cT3 tumors were nearly six times more likely to undergo mastectomy compared with patients with cT1 tumors (P = .003; OR = 5.74; 95% CI, 2.07-15.97). Moreover, patients older than 50 years of age (P < .001; OR = 2.84; 95% CI, = 1.93-4.16) were more likely to be offered mastectomy. No association between the type of surgery and pathological complete response (P = .351) was observed.ConclusionPretreatment clinical disease size remains a strong predictor of surgical management, whereas response to NAC appeared to play no role in the surgical decision, suggesting that the potential surgical benefits of NAC may be still under-recogonized in northwest China.     

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study)

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85–90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36–5.21, P = 0.004 for cN2–3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15–2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22–3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43–4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16–4.20, P = 0.017 for cT3–4 vs. cT1–2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48–6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53–13.14, P = 0.005 for cN2–3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12–4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31–5.97, P = 0.006 and HR 3.86, 95 % CI 1.13–24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.     

Somatic alterations of TP53, ERBB2, PIK3CA and CCND1 are associated with chemosensitivity for breast cancers

The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline‐taxane‐based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer‐related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases. TP53 mutation (P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2 amplification (P < 0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates. PIK3CA mutation (P = 0.040 for ypT0/isypN0) and CCND2 amplification (P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates (P = 0.043 for ypT0/is). Patients with TP53 mutation (?) PIK3CA mutation (?) ERBB2 amplification (+) CCND1 amplification (?), TP53 mutation (+) PIK3CA mutation (?) ERBB2 amplification (+) CCND1 amplification (?) or TP53 mutation (+) PIK3CA mutation (+) ERBB2 amplification (+) CCND1 amplification (?)had significantly higher pCR rates (P < 0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.     

Indications for Postmastectomy Radiation After Neoadjuvant Chemotherapy in ypN0 and ypN1-3 Axillary Node-Positive Women

Introduction

Downstaging with neoadjuvant chemotherapy (NAC) might obscure indications for postmastectomy radiation (PMRT). The degree of downstaging that results in local-regional recurrence (LRR) rates low enough to omit PMRT remains controversial. We examined the rate of LRR in women who received NAC who underwent mastectomy without PMRT.

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

BackgroundCombining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.Patients and methodsGeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).ResultsA total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23–76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ²P = 0.287), corresponding to OR = 1.45 (95% CI 0.80–2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06–4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.ConclusionsOur results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.Trial registrationClinicalTrials.gov number: NCT02685059.     

Patterns of Failure in Women Who Have Residual Nodal Disease After Neoadjuvant Chemotherapy for Breast Cancer According to Extent of Lymph Node Surgery

BackgroundOptimal surgical management of limited axillary nodal disease following neoadjuvant chemotherapy (NAC) for breast cancer is evolving. Concerns exist with respect to leaving residual disease in the axilla when omitting axillary lymph node dissection (ALND) in this setting. We sought to determine whether extent of nodal surgery altered patterns of failure and patient outcomes.Patients and MethodsWe identified 70 patients with breast cancer who were confirmed cN0 after NAC yet had residual nodal disease (ypN1) on sentinel lymph node biopsy (SLNB). Twenty-eight patients underwent SLNB alone and 42 underwent SLNB+completion (c)ALND in a non-randomized fashion. Most (n = 65) patients underwent adjuvant regional nodal irradiation (RNI). Detailed patterns of failure data were obtained for each patient.ResultsThe median follow-up was 43.5 months. There were 30 (43%) recurrences. Of these, 5 were isolated locoregional failures, and 24 were distant failures. There were no significant differences in local (P = .13), regional (P = .62), or distant (P = .47) failure between patients who underwent SLNB alone versus SLNB+cALND. Seventeen (24%) patients died. Overall survival was similar in both groups with median overall survival not reached for those who underwent SLNB and 109 months for those who underwent SLNB+cALND (P = .45).ConclusionsThere were no differences in patterns of recurrence among patients with 1 to 3 involved lymph nodes after NAC who underwent SLNB alone versus SLNB+cALND in the setting of RNI. We await the results of ongoing, prospective clinical trials to confirm the relative merits of RNI in lieu of cALND in these patients.     

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio in Different Phenotypes of Locally Advanced Breast Cancer During Neoadjuvant Systemic Treatment

PurposeNeutrophils are among the key cellular players in the inflammatory milieu produced in patients with breast cancer (BC), and strong evidence exists in terms of the prognostic value of assessing the neutrophil-to-lymphocyte ratio (NLR) in patients with BC. In this study we sought to determine whether the baseline NLR correlates with pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS) in patients with locally advanced BC in the neoadjuvant chemotherapy (NAC) setting.MethodsWe analyzed the pretreatment NLR from the first blood count of patients treated from 2007 to 2015 in terms of pCR, DFS, and OS in patients with locally advanced BC. Patients received standard medical care based on national guidelines.ResultsA total of 1519 patients were included in the study. Median age was 49 years (22-88). The cutoff point for NLR was 2.0. NLR was not associated with pCR or DFS. However, patients with high NLR had worse OS in the presence of triple-negative BC (105.9 months; 95% confidence interval [CI], 100.2-111.5] vs. 98.7 months; 95% CI, 91.1-106.3; P = .029), Her2 overexpression (114.0 months; 95% CI, 110.5-118.0 vs. 100.8 months; 95% CI 95.7-105.9; P = .019), and residual disease after NAC for both phenotypes. Multivariate analysis showed that NLR was independently associated with OS (hazard ratio, 1.4; 95% CI, 1.02-1.95; P = .037).ConclusionsPretreatment NLR in patients with locally advanced BC correlates with OS as an independent prognostic factor. This influence depends on phenotype and residual disease. Routine assessment of this parameter could be an easy and affordable tool for defining prognosis.