Paclitaxel,Carboplatin, and Trastuzumab in a Neo‐adjuvant Regimen for HER2‐positive Breast Cancer

To evaluate a nonanthracycline‐containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo‐adjuvant therapy for human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m², carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node‐positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty‐seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin–paclitaxel–trastuzumab neo‐adjuvant regimen is highly active in HER2‐positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines.     

Early Response to Neo‐adjuvant Chemotherapy in Carcinoma of the Breast Predicts Both Successful Breast‐Conserving Surgery and Decreased Risk of Ipsilateral Breast Tumor Recurrence

Abstract: Neo‐adjuvant chemotherapy enables us to increase the possibility of breast‐conserving surgery for large, bulky tumors. However, several studies have reported that ipsilateral breast tumor recurrences (IBTRs) occur more frequently after neo‐adjuvant chemotherapy than originally envisaged. Recently, it was demonstrated that clinical early response after neo‐adjuvant chemotherapy predicts pathological complete response. In this study, we assessed the association of clinical early response after neo‐adjuvant chemotherapy with successful breast‐conserving surgery and IBTR risk. Between 1995 and 2002, 114 patients with T 3.1–6 cm, N 0 or 1, M 0 breast cancer who were candidates for mastectomy but desired breast‐conserving surgery were treated with neo‐adjuvant chemotherapy. After two cycles of anthracycline‐based neo‐adjuvant chemotherapy and before surgery, breast tumors were measured by palpation or ultrasound. Clinical response after two cycles of chemotherapy was defined as positive when the largest tumor dimension was reduced by 30% or greater. Median follow‐up time was 72 months. After two cycles of neo‐adjuvant chemotherapy, 54 (47.4%) of 114 patients achieved an early response. Patients with the early response underwent breast‐conserving surgery significantly more frequently than those without the early response (78% versus 58%, p = 0.03). In addition, the early response was significantly correlated with selection of breast‐conserving surgery (odds ratio 3.8, p = 0.01) after adjustments for various clinicopathological factors. Patients without the early response showed significantly lower 6‐year IBTR‐free survival than patients with the early response (75% versus 97%, p = 0.02). In addition, patients with the early response showed significantly higher 6‐year disease‐free survival rates than those with the early response (p = 0.02). Multivariate analysis showed that the early response was a predictive factor of IBTR‐free survival, being independent of other clinicopathological factors. In conclusion, the early response to neo‐adjuvant chemotherapy may be a useful predictor of both selection of surgical method and IBTR risk.     

A Three‐Arm Randomized Phase II Study of Oral Vinorelbine Plus Capecitabine Versus Oral Vinorelbine and Capecitabine in Sequence Versus Docetaxel Plus Capecitabine in Patients with Metastatic Breast Cancer Previously Treated with Anthracyclines

Owing to the increased number of patients treated with anthracycline‐based adjuvant chemotherapy, there is a need for new effective and tolerable nonanthracycline regimens in metastatic breast cancer. Patients with HER2‐negative metastatic breast cancer previously treated with anthracyclines in (neo)adjuvant setting were randomized to fully oral 3 weekly cycles of the combination of oral vinorelbine with capecitabine (V + C), to the same drugs alternating every three cycles (V?C), or to the combination of docetaxel and capecitabine (D + C). V was given at 80 mg/m² (after the first cycle at 60 mg/m²) on days 1 and 8 in the V + C arm and weekly in the V?C arm, C at 1,000 mg/m² bid from days 1 to 14, and D on day 1 at 75 mg/m². The primary end point was disease control rate (CR + PR + NC ≥ 3 months). A total of 139 patients were randomly assigned to V + C (44 patients), V?C (47 patients), and D + C (48 patients). After an independent review, the disease control rate in the intent‐to‐treat population in the V + C, V?C, and D + C arms [95% CI] was 70.5% [54.8–83.2], 37.0% [23.2–52.5], and 70.8% [55.9–83.1], and the median overall survival 22.2, 19.4, and 24.2 months, respectively. When taken into account the disease control rate, the alternating V?C regimen seems to be less effective compared with V + C or D + C combinations. Combinations of V + C or D + C showed similar efficacy and a different toxicity profile; V + C induced less neutropenia, infection, hand‐foot syndrome, fatigue/asthenia, and alopecia, whereas D + C – less gastrointestinal toxicity. V + C combination constitutes a valuable fully oral alternative option to D + C in patients with metastatic breast cancer previously treated with anthracyclines in (neo)adjuvant setting, while offering the advantages of an all‐oral treatment.     

Pathologic Tumor Response of Invasive Lobular Carcinoma to Neo‐adjuvant Chemotherapy

Abstract: Neo‐adjuvant chemotherapy is used for locally advanced breast cancer patients with significant variation in tumor response. Our objective is to determine the clinicopathologic effect of neo‐adjuvant chemotherapy on invasive lobular carcinoma. A review of a single‐institution data base of women diagnosed with breast cancer identified 30 patients from 1999 to 2009 with operable invasive lobular carcinoma who received neo‐adjuvant chemotherapy. Patient demographics and clinicopathologic data were reviewed. Cases were reviewed by a single pathologist (NNE). Residual cancer burden class was determined for each case. Median patient age was 50 years (range 25–79). All tumors were hormone receptor positive and clinical stage II or III carcinomas. Most patients (53.3%) had combination anthracycline‐ and taxane‐based chemotherapy. Therapy‐related changes were noted within the tumor bed in 25 (83.3%) patients. Six (30%) of 20 patients with residual axillary disease had therapy‐related nodal changes. There were 11 patients with moderate residual disease (class II) and 18 (60%) with extensive (class III); there were no complete pathologic responses (class 0). Only one patient (3.3%) converted from mastectomy to breast‐conserving surgery. Four (13.3%) patients developed distant metastases; all had pleomorphic‐type, clinical stage III tumors with residual cancer burden III classification and developed distant disease in the 2 years after surgery (range 0–26 months). Median follow‐up time was 29.5 months (range 7–132). Patients with locally advanced pleomorphic‐type lobular carcinoma appear to develop early post‐treatment metastatic disease. Neo‐adjuvant chemotherapy did not appear to have significant impact on the surgical treatment of patients with invasive lobular carcinoma.     

Oncoplastic Mammoplasty as a Strategy for Reducing Reconstructive Complications Associated with Postmastectomy Radiation Therapy

Given the high complication rates in patients who require radiation therapy (XRT) after mastectomy and immediate reconstruction, and the low local recurrence rates following neo‐adjuvant chemotherapy and breast conservation therapy, we sought to determine if using neo‐adjuvant chemotherapy and oncoplastic mammoplasty as an alternative to mastectomy and immediate reconstruction is an effective strategy for reducing complication rates in the setting of XRT. A prospectively maintained data base was queried for patients who received neo‐adjuvant chemotherapy and XRT between 2001 and 2010 and underwent either oncoplastic mammoplasty or mastectomy with immediate reconstruction. Rates of postoperative complications between groups were compared using Fisher's exact test. Outcomes from 37 patients who underwent oncoplastic mammoplasty were compared to 64 patients who underwent mastectomy with immediate reconstruction. Mean follow‐up was 33 months (range 4–116 months). Rates of postoperative complications, including unplanned operative intervention for a reconstructive complication (2.7% versus 37.5%, p < 0.001), skin flap necrosis (10.8% versus 29.7%, p = 0.05), and infection (16.2% versus 35.9, p = 0.04) were significantly higher in the mastectomy group. Overall, 45.3% of patients who underwent mastectomy developed at least one breast complication, compared to 18.9% of patients who underwent oncoplastic mammoplasty (p = 0.01). If XRT is indicated after mastectomy, attempts should be made to achieve breast conservation through the use of neo‐adjuvant therapy and oncoplastic surgery in order to optimize surgical outcomes. Breast conservation with oncoplastic reconstruction does not compromise oncologic outcome, but significantly reduces complications compared to postmastectomy reconstruction followed by XRT.     

The Integrated Evaluation of the Results of Oncoplastic Surgery for Locally Advanced Breast Cancer

The optimal surgical management of locally advanced breast cancer (LABC) remains undefined. The aim of the study was to obtain long‐term results of oncoplastic surgery in terms of overall survival, loco‐regional recurrence, and quality of life in case of LABC. Prospective cohort study enrolled 60 patients with stage III breast cancer. Forty‐two (70%) patients received neo‐adjuvant chemotherapy, 28 patients were considered suitable for surgery as initial treatment option. Type II oncoplastic surgery was performed for all patients: hemimastectomy and breast reconstruction with latissimus dorsi flap – for 29 (48.3%), lumpectomy – 31 (51.7%), and reconstruction with subaxillary flap for four (6.7%), with bilateral reduction mammoplasty – 14 (23.3%) and with J‐plastic – 13 (21.7%) patients. Adjuvant chemotherapy and hormonal therapy followed surgery for all, except one, patients. Sequential radiotherapy was administered for all patients. The mean period of follow‐up was 86 months. Postoperative morbidity rate was 5%. Local‐regional recurrence was detected in six (10%) patients. After reoperation no local relapse was diagnosed. However, three of these patients had systemic dissemination of the disease. Distant metastasis was detected in 23 (38.3%) patients. Distant metastasis‐free survival at 5 years was 61.7%. Fourteen patients died (23.3%). A total of 87.2% of the patients had good and excellent esthetic outcome. Oncoplastic breast‐conserving surgery can be proposed for selected patients with LABC with acceptable complication, local recurrence rate, and good esthetic results.     

Efficacy of anthracycline/taxane‐based neo‐adjuvant chemotherapy on triple‐negative breast cancer in BRCA1/BRCA2 mutation carriers

This study aims to estimate the pathologic complete response (pCR) rate after neo‐adjuvant chemotherapy and to compare disease‐free survival (DFS) and overall survival (OS) between pCR and non‐pCR groups of patients with triple‐negative breast cancer (TNBC) and deleterious BRCA1 or BRCA2 mutation. We carried out a retrospective analysis of 53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation. All patients had been diagnosed with triple‐negative breast cancer (TNBC) between 1997 and 2014. Neo‐adjuvant therapy consisted of regimens that were based on anthracycline or an anthracycline‐taxane doublet. DFS included any relapse or second cancer. The Kaplan‐Meier method and the log‐rank test were used to compare pCR and non‐pCR groups. A pCR was observed in 23 (42.6% [95% CI, 29.2%‐56.8%]) of the TNBC included. The pCR rate was 38.3% [95% CI, 26%‐55%] among BRCA1 mutation carriers, and 66% among the 6 BRCA2 mutation carriers. Median follow‐up was 4.4 years (range 0.62‐16.2 years) and did not differ between the groups (P = .25). Fifteen relapses and six second cancers were recorded during the follow‐up period. Eleven deaths occurred, all of which were in the non‐pCR group. DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non‐pCR group. This study shows a high pCR rate after neo‐adjuvant therapy in BRCA‐mutated triple‐negative breast cancer, and the survival results confirm the prognostic value of pCR in this group. These outcomes should be considered as a basis of comparison to be used by future studies about new therapies in this domain.     

Predicting neo‐adjuvant chemotherapy response and progression‐free survival of locally advanced breast cancer using textural features of intratumoral heterogeneity on F‐18 FDG PET/CT and diffusion‐weighted MR imaging

Predicting response to neo‐adjuvant chemotherapy (NAC) and survival in locally advanced breast cancer (LABC) is important. This study investigated the prognostic value of tumor heterogeneity evaluated with textural analysis through F‐18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion‐weighted imaging (DWI). We enrolled 83 patients with LABC who had completed NAC and curative surgery. Tumor texture indices from pretreatment FDG PET and DWI were extracted from histogram analysis and 7 different parent matrices: co‐occurrence matrix, the voxel‐alignment matrix, neighborhood intensity difference matrix, intensity size‐zone matrix (ISZM), normalized gray‐level co‐occurrence matrix (NGLCM), neighboring gray‐level dependence matrix (NGLDM), and texture spectrum matrix. The predictive values of textural features were tested regarding both pathologic NAC response and progression‐free survival. Among 83 patients, 46 were pathologic responders, while 37 were nonresponders. The PET texture indices from 7 parent matrices, DWI texture indices from histogram, and 1 parent matrix (NGLCM) showed significant differences according to NAC response. On multivariable analysis, number nonuniformity of PET extracted from the NGLDM was an independent predictor of pathologic response (P = .009). During a median follow‐up period of 17.3 months, 14 patients experienced recurrence. High‐intensity zone emphasis (HIZE) and high‐intensity short‐zone emphasis (HISZE) from PET extracted from ISZM were significant textural predictors (P = .011 and P = .033). On Cox regression analysis, only HIZE was a significant predictor of recurrence (P = .027), while HISZE showed borderline significance (P = .107). Tumor texture indices are useful for NAC response prediction in LABC. Moreover, PET texture indices can help to predict disease recurrence.     

Loco‐regional Control After Neo‐adjuvant Chemotherapy and Conservative Treatment for Locally Advanced Breast Cancer Patients

Breast‐conserving treatment (BCT) has been validated for breast cancer patients receiving adjuvant chemotherapy. Our objective was to evaluate the difference in loco‐regional recurrence (LRR) rates between BCT and mastectomy in patients receiving radiation therapy after neo‐adjuvant chemotherapy (NCT). A retrospective data base was used to identify all patients with breast cancer undergoing NCT from 2002 to 2007. Patients with initial metastatic disease were excluded from this analysis. LRR was compared between those undergoing BCT and mastectomy. Individual variables associated with LRR were evaluated. Two hundred eighty‐four patients were included, 111 (39%) underwent BCT and 173 (61%) mastectomy. Almost all patients (99%) in both groups received postoperative radiation. Pathologic complete response was seen in 37 patients, of which 28 underwent BCT (p < 0.001). Patients receiving mastectomy had more invasive lobular carcinoma (p = 0.007) and a higher American Joint Committee on Cancer (AJCC) stage (p < 0.001) at diagnosis than those with BCT. At a median follow‐up of 6.3 years, the loco‐regional control rate was 91% (95% CI: 86–94%). The 10‐year LRR rate was similar in the BCT group (9.2% [95% CI: 4.9–16.7%]) and in the mastectomy group (10.7% [95% CI: 5.9–15.2%]; p = 0.8). Ten‐year overall survival (OS) rates (63% [95% CI: 46–79%] in the BCT group; 60% [95% CI: 47–73%] in the mastectomy group, p = 0.8) were not statistically different between the two patient populations. Multivariate analysis showed that AJCC stage ≥ III (HR: 2.6; 95% CI: 1.2–5.8; p = 0.02), negative PR (HR: 6; 95% CI: 1.2–30.6, p = 0.03), and number of positive lymph nodes ≥3 (HR: 2.5; 95% CI: 1.1–5.9; p = 0.03) were independent predictors of LRR. Ten‐year OS was similar in the BCT and in the mastectomy group (p = 0.1). The rate of LRR was low and did not significantly differ between the BCT and the mastectomy group after NCT. Randomized trials assessing whether mastectomy can be safely omitted in selected breast cancer patients (nonstage III tumors or those which do not require adjuvant hormone suppression) which respond to NCT are required.     

Single Institution trial of anthracycline‐ and taxane‐based chemotherapy for operable breast cancer: The ASTER study

The efficacy of anthracycline‐ and taxane‐based chemotherapy for perioperative treatment of breast cancer (BC) has been established. No superiority of a cytotoxic regimen has been demonstrated, provided that administration of an anthracycline and a taxane is warranted. The ASTER study was designed to investigate the safety of 6 months of perioperative chemotherapy with Doxorubicin and Paclitaxel, followed by Cyclophosphamide, Methotrexate, and 5‐Fluorouracil. ASTER enrolled patients with cT2‐3 N0‐1 or pT1‐2 N1‐3 BC, from November 2008 to August 2011. Treatment consisted of Doxorubicin 60 mg/sm, Paclitaxel 200 mg/sm q21 (AT) for three cycles followed by Cyclophosphamide 600 mg/sm, Methotrexate 40 mg/sm, 5‐Fluorouracil 600 mg/sm d1,8 q28 (CMF) for three cycles, in either neo‐adjuvant or adjuvant setting. All HER‐positive patients received targeted therapy with Trastuzumab for 1 year. Disease‐free and overall survival (DFS and OS, respectively) were estimated according to Kaplan‐Meier method. Three hundred and thirty patients were enrolled, where 77.9% of cases were treated in an adjuvant setting; 65.5% received breast conservative surgery, 72.4% axillary dissection. 75.5% of cases presented estrogen receptor positivity, 66.7% progesterone receptor positivity; 18.5% of patients presented HER2‐positive BC, 16.1% triple negative disease. Twenty‐eight (8.5%) developed grade III‐IV hematologic toxicity; nine patients (2.7%) developed grade III neurological toxicity. Loco‐regional DFS was 99.6% at 1 year, 97.1% at 5 years, 95.9% at 7 years. Corresponding distant DFS was 98.4%, 90.2%, and 88.8%. One, 5, and 7‐year OS was 99.6%, 94.9%, and 91.2%, respectively. Chemotherapy with ATx3→CMFx3 is confirmed safe and effective at 6.7 years follow‐up. These results appear comparable to those reported in regulatory trials of most commonly prescribed anthracycline and taxane‐based regimens.     

Time from Completion of Neo‐adjuvant Chemotherapy to Surgery: Effects on Outcomes in Breast Cancer Patients

There is no consensus on the ideal time interval between the completion of neo‐adjuvant chemotherapy (NAC) and definitive surgery for patients with breast cancer. This study sought to determine the ideal time interval from completion of systemic therapy to surgery in an attempt to define a best practice. A retrospective analysis of all patients undergoing NAC for Stage I‐III breast cancer from 1998‐2010 was undertaken. Analysis of all demographic and clinical information was performed, with emphasis on interval from completion of systemic therapy to definitive surgical management. Three hundred and eighty eight patients met the inclusion criteria with a median age of 50 (61.9% white, 33.8% black and 4.3% other). Overall, 2.8% of patients were Stage I, 57.2% Stage II and 40% Stage III. Median follow‐up was 85 months. Pathologic response to systemic therapy was complete in 20.6%, partial in 67.8% and no response or progression in 11.6%; responders (pCR or pPR) were noted to have significantly improved Disease free survival (DFS) and Overall survival (OS). Patients undergoing surgical intervention 4‐6 weeks after completion of NAC were noted to have a trend towards improved DFS and OS on multivariable analysis. These findings were also observed in the nonlinear relationship between survival risk and surgery time window using martingale residual plots. Timing of surgical intervention following the receipt of NAC may not appear to affect DFS or OS.     

First-line bevacizumab and eribulin combination therapy for HER2-negative metastatic breast cancer: Efficacy and safety in the GINECO phase II ESMERALDA study

PurposeCombining bevacizumab with paclitaxel significantly improves progression-free survival (PFS) versus paclitaxel alone in HER2-negative metastatic breast cancer (MBC). Eribulin is active and tolerable in pretreated MBC. To assess whether eribulin may offer a more tolerable yet effective combination partner for bevacizumab, we evaluated a bevacizumab/eribulin combination regimen as first-line therapy for MBC.MethodsIn this single-arm phase II study, patients with histologically confirmed HER2-negative MBC and no prior chemotherapy for MBC received eribulin 1.23 mg/m² on days 1 and 8 every 3 weeks for ≥6 cycles plus bevacizumab 15 mg/kg on day 1 every 3 weeks until disease progression. The primary endpoint was non-progression rate at 1 year. Secondary endpoints included objective response rate (ORR), PFS, and safety.ResultsThe median age of the 61 treated female patients was 59 years, 16% had triple-negative MBC, 30% had ≥3 metastatic sites, and 71% had received prior (neo)adjuvant chemotherapy. Patients received a median of six eribulin and nine bevacizumab cycles. The non-progression rate at 1 year was 32% (95% confidence interval [CI]: 20–43%), ORR was 47% (95% CI: 34–60%), and median PFS was 8.3 months (95% CI: 7.0–9.6 months). The only grade ≥3 clinical adverse events in >5% of patients were hypertension (39%), neutropenia (26%), thrombosis (10%), and paresthesia/dysesthesia (7%).ConclusionFirst-line eribulin/bevacizumab combination therapy showed interesting activity in MBC with an acceptable safety profile, including a particularly low incidence of high-grade neuropathy.     

Added Value of Contrast‐Enhanced Spectral Mammography in Postscreening Assessment

To assess the value on diagnostic and treatment management of contrast‐enhanced spectral mammography (CESM), as adjunct to mammography (MG) and ultrasound (US) in postscreening in a breast cancer unit for patients with newly diagnosed breast cancer or with suspicious findings on conventional imaging. Retrospective review of routine use of bilateral CESM performed between September 2012 and September 2013 in 195 women with suspicious or undetermined findings on MG and/or US. CESM images were blindly reviewed by two radiologists for BI‐RADS^® assessment and probability of malignancy. Each lesion was definitely confirmed either with histopathology or follow‐up. Two hundred and ninety‐nine lesions were detected (221 malignant). CESM sensitivity, specificity, positive‐predictive value and negative‐predictive value were 94% (CI: 89–96%), 74% (CI: 63–83%), 91% (CI: 86–94%) and 81% (CI: 70–89%), respectively, with 18 false positive and 14 false negative. CESM changed diagnostic and treatment strategy in 41 (21%) patients either after detection of additional malignant lesions in 38 patients (19%)—with a more extensive surgery (n = 21) or neo‐adjuvant chemotherapy (n = 1)—or avoiding further biopsy for 20 patients with negative CESM. CESM can be performed easily in a clinical assessment after positive breast cancer screening and may change significantly the diagnostic and treatment strategy through breast cancer staging.     

Neo‐Adjuvant chemotherapy and its affects to the axilla—Can we safely downgrade axillary surgery to mirror the approach in the breast

The use of neo‐adjuvant chemotherapy (NACT) to downgrade surgery in the breast from mastectomy to breast‐conserving surgery is well‐established. In certain patients, the use of adjuvant axillary radiotherapy can be safe and effective in place of axillary node clearance. What remains less clear are the alternative surgical options to the axilla following NACT. The aim of this study was to examine the effects of NACT in the axilla and whether downgrading axillary node clearance to axillary conserving surgery to mirror the approach in the breast may be a viable and safe practice. Patients undergoing neo‐adjuvant chemotherapy were identified over a seven‐year period between 2010 and 2017. Surgical plans were compared with pre‐ and post‐chemotherapy. Histological information at the time of diagnosis was compared to surgical excision specimens. 349 patients were included for analysis, and 264 had axillary status documented at diagnosis. The average patient age was 51 years, and Grade 3, ER‐positive, and Her2‐negative cancers made the biggest histological subgroups. Complete pathological response (CPR) was seen in the breast in 27% of cases. 19% of patients requiring mastectomy had their surgery downgraded. Following NACT, axillary CPR was seen in 42% of patients and residual axillary nodal burden was limited to four nodes in 73% of patients. Axillary conserving surgery may be a safe alternative surgical approach in the downstaged axilla following neo‐adjuvant chemotherapy. Advances in perioperative identification of suspicious nodes may be needed to facilitate progress.     

Predictive factors for omitting lymphadenectomy in patients with node‐positive breast cancer treated with neo‐adjuvant systemic therapy

A pathologic complete response (pCR) in the axilla occurs in 30%‐40% of patients with initially node‐positive breast cancer after neo‐adjuvant chemotherapy (NACT). Debate persists about whether to perform systematic axillary lymphadenectomy (ALND) in patients with initial node‐positive disease and clinical complete response after NACT. We aimed to identify predictive factors of axillary pCR (ypN0) after NACT. This retrospective study analyzed data for all patients with initial biopsy‐proven node‐positive disease who underwent ALND after NACT between June 2008 and December 2016 at our institution. Clinical and pathologic features, recurrence and specific mortality rates were compared between patients who achieved an axillary pCR and those who did not (ypN0 vs ypN+, respectively). A total of 331 patients were included, of whom 128 (38.7%) became ypN0 after NACT. Among patients with >2 suspicious axillary lymph nodes before treatment, 54 (38%) achieved ypN0 status. The independent predictors of ypN0 were Ki‐67 > 30 (OR 1.98; 95% CI, 1.146‐3.381), HER2 positivity (OR 2.6; 95% CI, 1.354‐5.108), nonluminal molecular‐like subtype (OR 4.15; 95% CI, 2.068‐5.108), and clinical complete response, defined as negative clinical and ultrasonographic findings (OR 2.8; 95% CI, 1.110‐7.081). After a mean follow‐up of 61 months, distant disease‐free and overall survival rates were higher in patients with ypN0 disease (HR 4.14; 95% CI, 2.03‐8.43) than ypN+ patients. Complete clinical response and the presence of nonluminal molecular‐like subtypes independently predicted ypN0. Patients meeting these criteria might be suitable form omitting ALND and just performing targeted axillary procedures to patients meeting these criteria.     

Primary Large Cell Neuroendocrine Carcinoma of the Breast,a Case Report with an Unusual Clinical Course

Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34‐years‐old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline‐containing neo‐adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo‐adjuvant chemotherapy, the patient underwent breast‐conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo‐adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options.     

Women with Locally Advanced Breast Cancer are Not at Higher Risk for Contralateral Synchronous Breast Cancer

Abstract: Breast magnetic resonance imaging (MRI) may provide a more accurate assessment of synchronous contralateral breast cancer in select cohorts of patients. The utility of this imaging technique for detecting synchronous contralateral breast cancers in patients with locally advanced breast cancer (LABC) has not previously been described. We report our experience in assessing contralateral disease in a cohort of women with LABC who had clinical assessment, mammography, ultrasound, and MRI prior to neo‐adjuvant therapy. Patients, who presented with LABC, stage IIB (T3N0), stage III A/B, were identified from a prospectively kept data base at a single tertiary care centre between November 2001 and August 2005. Charts were retrospectively reviewed and demographic, imaging and pathologic variables were abstracted. One hundred and one female patients with LABC were identified (median age 49). One hundred of 101 patients presented with a clinically obvious LABC. Three patients had LABC that was not visualized mammographically but was detected on ultrasound and MRI. Seventeen of 101 patients (17%) had contralateral imaging findings that required biopsy for diagnosis. Of the contralateral biopsies, 41% (7/17) were malignant. These malignant lesions were identified clinically in 4/7 patients, on 7/7 ultrasounds, 7/7 mammograms, and 5/5 MRI. Overall, 7% (7/101) patients had malignant synchronous contralateral disease. In our LABC patient cohort, 7% of patients presented with malignant contralateral disease. The incidence of contralateral disease in women with LABC is comparable with patients who present with early stage breast cancer. No single screening technique, ultrasound, mammogram or MRI, appeared to be superior for identifying contralateral synchronous malignancy.     

Capecitabine and Vinorelbine as an All-Oral Chemotherapy in HER2-Negative Locally Advanced and Metastatic Breast Cancer

BACKGROUND: The oral formulation of vinorelbine together with capecitabine allows for an all-oral combination chemotherapy which promises to raise quality of life of patients with advanced breast cancer. PATIENTS AND METHODS: Patients with HER2-negative, locally advanced, inoperable or metastatic breast cancer were included in this prospective observational trial (treatment schedule: capecitabine 500 mg/m2 twice daily, days 1-14; vinorelbine 60 mg/m2, days 1+8; repeated in 3-week cycles). RESULTS: All 32 patients (median age 50 years) were evaluable for toxicity, and 30 patients for response. Twentyfour patients received therapy as first-line treatment, and 8 patients as beyond first-line treatment. Median time to progression was 8 months, and median overall survival was 32 months. Complete response was observed in 1 patient (3%), partial response in 10 patients (33%), and disease stabilization for more than 6 months (SD > 6) in 10 patients (33%). This results in an overall response rate (ORR) of 37% and a clinical benefit rate (ORR + SD > 6) of 70%. The only grade 3/4 toxicities were neutropenia (19%) and hand-foot syndrome (9%). CONCLUSIONS: The all-oral combination of capecitabine/vinorelbine at this schedule appears to be an effective, well-tolerated regimen for treatment of advanced breast cancer, and offers a promising alternative to single-agent capecitabine and vinorelbine as well as intravenous polychemotherapy.     

Implications of Anthracycline‐Resistant and Taxane‐Resistant Metastatic Breast Cancer and New Therapeutic Options

Abstract: Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P‐glycoprotein, as well as alterations in β‐tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug‐resistance mechanisms, has demonstrated preclinical activity in drug‐resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment‐related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53–54%) and reversible peripheral sensory neuropathy (14–16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug‐resistant breast cancer and in specific patient subsets is warranted.     

Metronomic oral chemotherapy with cyclophosphamide plus capecitabine combined with trastuzumab (HEX) as first line therapy of HER-2 positive advanced breast cancer: A phase II trial of the Gruppo Oncologico Italia Meridionale (GOIM)

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.