Prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer by combining magnetic resonance imaging and core needle biopsy

BackgroundPathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI.MethodsIn this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated.ResultsOf the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis.ConclusionIn cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.     

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.     

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.     

HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis

BackgroundHER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT).MethodsA systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins’ I² was used to quantify heterogeneity.ResultsSixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001, I² = 33%), in HR+ (OR = 3.61, p < 0.001, I² = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I² = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR = 5.52, p < 0.001, I² = 0%) and in HR + disease (OR = 4.08, p = 0.001, I² = 0%). HR-negative status was significantly associated with pCR compared to HR + status in all patients (OR = 2.41, p < 0.001, I² = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I² = 0%).ConclusionsThe HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.     

Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial

BackgroundThe neoadjuvant phase III GeparSepto study showed that substituting nab-paclitaxel for standard solvent-based paclitaxel significantly improved the pathologic complete response (pCR) rate achieved with a sequential neoadjuvant chemotherapy regimen of paclitaxel, epirubicin, and cyclophosphamide for high-risk primary breast cancer. Recent trials demonstrated that in HER2+ breast cancer pCR can be increased by using pertuzumab in addition to trastuzumab and chemotherapy. The present analysis focuses on efficacy and safety data from the subset of patients with HER2+ tumors from the GeparSepto trial (n = 396) in comparison to the HER2- cohort.Patients and methodsPatients with histologically confirmed breast cancer (n = 1206) received four cycles of weekly paclitaxel [either solvent-based (Pac) or nab-paclitaxel (nab-Pac), according to randomization] followed by 4 cycles of epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² q3w, with concurrent trastuzumab and pertuzumab q3w for those with HER2+ tumors. The primary endpoint was pCR defined as ypT0 ypN0.ResultsHigher rates of pCR were achieved in HER2+ than in HER2- tumors (57.8% versus 22.0%,P < 0.0001), with the highest rate in the HER2+/HR- cohort (71.0%; 66.7% Pac, 74.6% nab-Pac). In HER2+/HR+ tumors, the pCR rate was 52.9% (49.7% Pac, 56.4% nab-Pac). Grade ≥3 toxic effects were significantly more common in HER2+ than in HER2- patients, with grade 3–4 diarrhea in 7.6% versus 0.9% (P < 0.001) and febrile neutropenia in 6.3% versus 3.3% (P = 0.023) of patients. Left ventricular ejection fraction decreases from baseline were uncommon, with 2.0% versus 0.4% of patients showing decreases to <50% along with a ≥10% decrease from baseline.ConclusionIn HER2+ early breast cancer, a dual HER2-targeted combination of pertuzumab and trastuzumab, together with taxane–epirubicin–cyclophosphamide neoadjuvant chemotherapy, achieved high rates of pCR.     

ypT0N+ status in oesophageal cancer patients: Location of residual metastatic lymph nodes with regard to the neoadjuvant radiation field

IntroductionA subset of oesophageal cancer patients has residual nodal disease despite complete pathologic response of the primary tumour after neoadjuvant chemoradiation and resection. The aim of this study was to determine the exact location of metastatic nodes with regard to the neoadjuvant radiation field and to assess progression-free (PFS) and overall survival (OS) in this group of patients.Materials and methodsFrom January 2010 to January 2017, complete tumour responders (ypT0) after neoadjuvant chemoradiotherapy and oesophagectomy were identified from a prospective database and grouped according to residual nodal disease (ypT0N + or ypT0N0). Radiation fields were analysed for location of the metastatic nodes and PFS and OS were determined.ResultsIn a total of 192 patients, 53 complete responders (ypT0) were identified. Of those, 11 patients (20.8%) were ypT0N+ with a total of 12 metastatic nodes: 8 (66.7%) located within the neoadjuvant radiation field and 4 (33.3%) located outside this field. Although not statistically significant, 1- and 2-year PFS were worse in ypT0N + patients (ypT0N+ 64.3% vs. ypT0N0 84.4%; ypT0N+ 48.2% vs. ypT0N0 80.7%, respectively; p = 0.051), just as 1- and 2-year OS rates, however, to a lesser extent (ypT0N+ 75.0% vs. ypT0N0 76.3%; ypT0N+ 75.0% vs. ypT0N0 72.9%, respectively; p = 0.956).ConclusionMost ypT0N + lymph nodes are located within the neoadjuvant radiation field. Although a small heterogeneous population was included, this might be due to an inadequate response to neoadjuvant chemoradiotherapy leading to a trend towards worse PFS and OS in ypT0N + patients. Larger studies need to validate our findings.     

Neoadjuvant treatment with docetaxel plus lapatinib,trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study

Five trials assessed lapatinib and trastuzumab (L+T) combined with paclitaxel-containing chemotherapy regimens. They showed high pathological complete response rates, but at the cost of toxicity. This trial assesses L+T combined with docetaxel. The use of docetaxel rather than paclitaxel does not avoid much of the toxicity. Regarding efficacy our results are very consistent with NSABP-B41 trial.BackgroundNeoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab.Patients and methodsPatients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies.ResultsFrom October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%).Frequency (%) of the most common grade 3–4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8.ConclusionsThis study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity.ClinicalTrials.govNCT00450892.     

Magnetic Resonance Imaging Combined With Second-look Ultrasonography in Predicting Pathologic Complete Response After Neoadjuvant Chemotherapy in Primary Breast Cancer Patients

Background

Magnetic resonance imaging (MRI) or ultrasonography (US) alone is limited in the ability to predict the pathologic complete response (pCR) accurately after neoadjuvant chemotherapy (NAC). The aim of the present study was to predict the pCR using MRI combined with second-look US in primary breast cancer patients.

Can a pathological complete response of breast cancer after neoadjuvant chemotherapy be diagnosed by minimal invasive biopsy?

BackgroundThis study aimed to explore the ability of a minimal invasive biopsy to diagnose a pathological complete response (pCR = ypT0) in the breast.MethodsUltrasound-guided, vacuum-assisted, minimal invasive biopsy (VAB) was performed in 50 patients after neoadjuvant chemotherapy and before breast surgery. Negative predictive values (NPV) and false negative rates (FNR) to predict a pCR in surgical specimen were the main outcome measures. To assess the possible sampling error, the representativeness of the sample was evaluated by the biopsy performing physician (subjectively based on the visibility in ultrasound), by radiography of the biopsy specimen, and by the pathologist (based on histopathology).ResultsThe cohort (n = 50) consisted of 15 (30%) triple negative breast cancers, 13 (26%) human epidermal growth factor receptor 2 (HER2) positive and 22 (44%) hormone receptor positive/HER2 negative cancers. ypT0 was diagnosed in 23 (46%) cases. In the overall cohort (n = 50), VAB yielded an NPV of 76.7% and an FNR of 25.9%. Given a representative VAB sample, according to the histopathological evaluation (n = 38), the NPV was 94.4% (95% CI 87.1–100.0) and the FNR 4.8% (95% CI 0.0–11.6). Non-representative VABs were mainly due to bad visibility of the target lesion in ultrasound.ConclusionA VAB can accurately diagnose a pCR, given a histopathologically representative sample.     

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer

BackgroundHER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.Patients and methodsBaseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).ResultsThirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031).ConclusionsOur findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.     

Predictors of nodal metastases in early stage HER2+ breast cancer: Deciding on treatment approach with neoadjuvant chemotherapy vs. upfront surgery

BackgroundThe purpose of this study is to evaluate preoperative predictors of nodal metastases in patients with early-stage, HER2-positive (HER2+) breast cancer.MethodsThe SEER Database was queried to identify women with a first diagnosis of stage I-II (T1-T2) HER2-positive breast cancer treated with upfront surgery in 2018. Multivariable logistic regression was used to identify clinical characteristics independently associated with nodal involvement.ResultsOverall, 3333 women with stage I-II HER2+ breast cancer met inclusion criteria and were included in the study. The median age at diagnosis was 59 years (IQR, 51–69 years). Most patients underwent breast-conserving surgery (60.9%), with a median of 3 (IQR 2–4) axillary lymph nodes removed. On final pathology, 762 (22.9%) of T1-T2 HER2+ patients were node positive; 2.7% pN0[i+], 3.7% pN1mi, 15.1% pN1, and 1.4% pN2. Women less than 40 years and those between 40 and 49 years showed the highest proportion of axillary lymph node metastasis, in 33.7% and 30.7% respectively, and declining with age (p < 0.001). Patients with triple-positive breast cancer had the highest rates of nodal involvement (24.8%), compared to 20.7% ER+/PR-/HER2+ and 19.6% of HER2-enriched patients (p = 0.006). On adjusted analysis, age, biologic subtype, tumour size, and type of surgery remained independent predictors of nodal involvement. On subgroup analysis, women under age 50 with T1c HER2-enriched or triple-positive breast cancer had a 33% and 35% incidence of nodal involvement, which declined with age.ConclusionsThe likelihood of pathologic nodal involvement in early-stage HER2+ breast cancer is contingent on age, ER/PR status, and tumour size.     

Locoregional and Distant Outcomes in Women With cT1-3N1 Breast Cancer Treated With Neoadjuvant Chemotherapy With or Without Adjuvant Radiotherapy

BackgroundWe evaluated the impact of postmastectomy radiotherapy (PMRT) or supraclavicular radiation therapy (SCV RT) in women with cT1-3N1 breast cancer (BC) who became node negative (ypN0) after neoadjuvant chemotherapy (NAC).Patients and MethodsWe retrospectively reviewed 485 women treated with NAC for BC between 2005 and 2019. Radiation treatment fields were reviewed in detail. Pathologic complete response (pCR) was defined as ypT0/Tis ypN0. Patients who had residual nodal disease were defined as ypN+. Those who achieved complete response in the lymph nodes but not in the breast were defined as ypT+ypN0.ResultsAfter excluding patients with cT4 and cN0 disease at diagnosis, a total of 185 patients with cT1-3N1 BC were included. Patients were more likely to receive PMRT if they had ypN+ disease (P < .001) and/or lymphovascular invasion (P = .03). Patients who underwent lumpectomy were more likely to receive SCV RT if they did not achieve pCR (P = .04) and/or if they had ypN+ disease (P = .01). The 5-year rates of locoregional recurrence (LRR) were 15% for all patients, 14% for patients who attained ypT+ypN0, and 5% for patients who achieved pCR. Of ypT+ypN0 patients (n = 98), 53 received PMRT or SCV RT and 45 did not. For these patients, there were no differences in LRR based on whether a patient did or did not receive PMRT or SCV RT (P = .23).ConclusionRecommendations for or against PMRT or SCV RT after NAC vary based on final pathologic response. We await the results of ongoing randomized clinical trials to help guide clinical decision making in this context.     

Characterizing Occult Nodal Disease Within a Clinically Node-Negative,Neoadjuvant Breast Cancer Population

BackgroundNeoadjuvant therapy aims to preoperatively downstage breast cancer patients. We evaluated nodal upstaging in clinically node-negative (cN0) patients receiving neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET).MethodscN0 patients undergoing neoadjuvant therapy from 2009 to 2018 were reviewed. Univariate and multivariate analyses evaluated rates of nodal upstaging.ResultsA total of 228 cN0 patients with a mean age of 55 years underwent neoadjuvant therapy for Stage I-III invasive carcinoma. Subtypes included ER+/HER2- = 93 (40%), HER2+ = 61 (27%), and triple negative (TNBC) = 74 (33%). Among ER+/HER2- patients, 65 (70%) underwent NET. Overall, 49 patients (21%) were upstaged due to occult nodal disease. Factors associated with higher rates of occult nodal disease included advanced stage on initial presentation (P = .008), larger presenting tumor size (P = .009), low/intermediate tumor grade (P = .025), and ER+/HER2- subtype (P < .001); incidence of occult nodal disease by subtype included: ER+/HER2- = 37%, HER2+ = 15%, TNBC = 8%. Patients experiencing a breast pCR had a significantly lower rate of nodal upstaging compared to those with residual tumor (4% vs. 96%, P < .001). On multivariate analysis, ER+/HER- patients exhibited higher risk of occult nodal disease when compared to patients with HER2+ (odds ratio [OR] = 3.4, 95% CI, 1.2-9.8, P = .003) and TNBC (OR = 5.7, 95% CI, 1.7-19.6, P = .003). Comparing NAC vs. NET in ER+/HER2- patients showed no difference in rates of occult nodal disease (39% vs. 35%, P = .13).ConclusionsER+/HER2- subtype carries higher risk for occult nodal disease after neoadjuvant therapy; NAC versus NET in these patients does not affect nodal upstaging.     

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.     

Efficacy and safety of trastuzumab,lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy,and with or without hormone therapy for HER2-positive primary breast cancer: a randomised,five-arm,multicentre, open-label phase II trial

Background

Dual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease.

Methods

We designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or oestrogen receptor (ER)+ disease. The primary endpoint was comprehensive pCR (CpCR) rate. Among the secondary endpoints, pCR (yT0-isyN0) rate, safety, and clinical response were evaluated.

Results

In total, 215 patients were enrolled; 212 were included in the full analysis set (median age 53.0 years; tumour size = T2, 65%; and tumour spread = N0, 55%). CpCR was achieved in 101 (47.9%) patients and was significantly higher in ER? patients than in ER+ patients (ER? 63.0%, ER+ 36.1%; P = 0.0034). pCR with pN0 was achieved in 42.2% of patients (ER? 57.6%, ER+ 30.3%). No significant difference was observed in pCR rate between prolonged exposure groups and standard groups. Better clinical response outcomes were obtained in the prolongation phase of the anti-HER2 therapy. No surplus was detected in pCR rate by adding endocrine treatment. No major safety concern was recognised by prolonging the anti-HER2 treatment or adding endocrine therapy.

Conclusions

This study confirmed the therapeutic impact of lapatinib, trastuzumab, and paclitaxel therapy for each ER? and ER+ subgroup of HER2+ patients. Development of further strategies and tools is required, particularly for luminal HER2 disease.

     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer

BackgroundAlthough 1% has been used as cut-off for estrogen receptor (ER) positivity, several studies have reported that tumors with ER < 1% have characteristics similar to those with 1% ≤ ER < 10%. We hypothesized that in patients with human epidermal growth factor 2 (HER2)-negative breast cancer, a cut-off of 10% is more useful than one of 1% in discriminating for both a better pathological complete response (pCR) rate to neoadjuvant chemotherapy and a better long-term outcome with adjuvant hormonal therapy. Our objectives were to identify a percentage of ER expression below which pCR was likely and to determine whether this cut-off value can identify patients who would benefit from adjuvant hormonal therapy.Patients and methodsPatients with stage II or III HER2-negative primary breast cancer who received neoadjuvant chemotherapy followed by definitive surgery between June 1982 and June 2013 were included. Logistic regression models were used to assess the association between each variable and pCR. Cox models were used to analyze time to recurrence and overall survival. The recursive partitioning and regression trees method was used to calculate the cut-off value of ER expression.ResultsA total of 3055 patients were analyzed. Low percentage of ER was significantly associated with high pCR rate (OR = 0.99, 95% CI = 0.986–0.994,P<0.001). The recommended cut-off of ER expression below which pCR was likely was 9.5%. Among patients with ER ≥ 10% tumors, but not those with 1%≤ER < 10% tumors, adjuvant hormonal therapy was significantly associated with long time to recurrence (HR = 0.24, 95% CI = 0.16–0.36,P<0.001) and overall survival (HR = 0.32, 95% CI = 0.2–0.5,P<0.001).ConclusionStage II or III HER2-negative primary breast cancer with ER < 10% behaves clinically like triple-negative breast cancer in terms of pCR and survival outcomes and patients with such tumors may have a limited benefit from adjuvant hormonal therapy. It may be more clinically relevant to define triple-negative breast cancer as HER2-negative breast cancer with <10%, rather than <1%, of ER and/or progesterone receptor expression.     

Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in operable breast cancer: A prospective cohort study

Purpose

Diagnostic methods to evaluate the response to neoadjuvant chemotherapy (NAC) for breast cancer have not been established. Dedicated breast PET (DbPET) is a high-resolution molecular breast imaging method, and we investigated the capability of DbPET to predict residual primary tumors after NAC compared with whole-body PET (WBPET).

Neoadjuvant,anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative,early-stage breast cancer: a multicentric analysis of rates of pathologic complete response and survival

Introduction: Triple-negative breast cancer (TNBC) has the highest mortality rates of all subtypes. Anthracycline and taxane regimens yield unsatisfactorily low rates of pathologic complete response (pCR) and are often not feasible in cardiac comorbidity. This study seeks to increase pCR and survival by introducing platin agents.

Patients and Methods: In this multicentric, open-label study with six cycles of docetaxel (75?mg/m²) and carboplatin AUC 6 q3w, patients were unwilling or unsuitable for anthracycline-based regimens. Primary endpoint was pCR (ypT0/ypTis ypN0) and survival.

Results: pCR rate was 50%. After 2 and 5?years, overall survival (OS) was 96.7 and 89.7%, disease-free-survival (DFS) 96.7 and 85.7%, DDFS 96.7 and 89.6%. Grade 3/4 toxicities were rare. Ninety-three per cent of patients completed six cycles. No toxicity-related treatment discontinuation or febrile neutropaenia was recorded.

Conclusion: This regimen is highly effective and feasible in TNBC and may be combined with anthracyclines.