MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Efficacy of neoadjuvant treatment with or without pertuzumab in patients with stage II and III HER2-positive breast cancer: a nationwide cohort analysis of pathologic response and 5-year survival.

BACKGROUND: Pathologic complete response (pCR) rates in early stage HER2-positive breast cancer improved after pertuzumab was added to neoadjuvant treatment. However, survival benefit is less-well established and seems mostly limited to node-positive patients. We used national cancer registry data to compare outcomes of patients treated with and without pertuzumab. METHODS: We identified stage II-III HER2-positive breast cancer patients treated with neoadjuvant trastuzumab-based chemotherapy between November 2013 until January 2016 from the Netherlands Cancer Registry. During that period pertuzumab was only available in the 37 hospitals that participated in the TRAIN-2 study. Missing grade and pCR-status were obtained from the Dutch Pathology Registry (PALGA) and cause of death from Statistics Netherlands. We used multiple imputation to impute missing data, multivariable logistic regression to evaluate the association between pertuzumab and pCR (ypT0/is, ypN0) and multivariable Cox regression models for overall survival and breast cancer specific survival (BCSS). RESULTS: We identified 1124 patients of whom 453 received pertuzumab. Baseline characteristics were comparable, although tumor grade was missing more often in patients treated without pertuzumab (12% vs. 2%). Pertuzumab improved pCR rates (41% vs 65%, adjusted odds ratio [aOR] 2.91; 95% CI:2.20-3.94). After a median follow-up of 6.0 years, 5-year BCSS rates were 95% and 98% respectively (adjusted hazard ratio [aHR]: 0.58; 95% CI:0.36-0.95). Younger patients derived more benefit from pertuzumab, but no other significant interactions were found. CONCLUSION: These results support earlier data of a small survival benefit with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy which is most meaningful in younger patients.

Pathologic response of ductal carcinoma in situ to neoadjuvant systemic treatment in HER2-positive breast cancer.

PURPOSE: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. METHODS: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. RESULTS: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response. CONCLUSIONS: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial.

IMPORTANCE: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade. OBJECTIVE: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. INTERVENTIONS: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. MAIN OUTCOMES AND MEASURES: Three-year EFS, OS, and safety. RESULTS: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia. CONCLUSIONS AND RELEVANCE: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01996267.

Adjuvant chemotherapy in small node-negative triple-negative breast cancer.

BACKGROUND: Recommendations on adjuvant chemotherapy in pT1N0M0 triple-negative breast cancer (TNBC) differ among international guidelines owing to lack of randomized trial data. We evaluated associations of adjuvant chemotherapy with a long-term outcome in a population-based cohort of pT1N0M0 TNBC. METHODS: All patients diagnosed with pT1N0M0 TNBC in the Netherlands between 2005 and 2016 were identified from the Netherlands Cancer Registry. Patient, tumour and treatment characteristics were recorded. The date and cause of death were obtained from Statistics Netherlands. We used multivariable Cox regression models to evaluate associations of adjuvant chemotherapy with breast cancer-specific survival (BCSS) and overall survival (OS), adjusted for baseline characteristics and performed sensitivity analyses using propensity score (PS) weighting. RESULTS: We identified 4366 patients: 284 with pT1a, 923 with pT1b and 3159 with pT1c tumours. Adjuvant chemotherapy was administered in 53% of patients. Patients receiving chemotherapy had more unfavourable baseline characteristics including younger age, larger tumours and higher tumour grade. At 8.2 years median follow-up (interquartile range = 5.8-10.9), 671 patients had died, of whom 311 because of breast cancer. After adjustment for baseline characteristics, chemotherapy was associated with improved BCSS (adjusted hazard ratio [aHR] = 0.65; 95% confidence interval [CI] = 0.48-0.89). The effect of chemotherapy differed by tumour size (pT1a: aHR = 4.28, 95% CI = 1.12-16.44; pT1b: aHR = 1.12, 95% CI = 0.51-2.49; pT1c: aHR = 0.60, 95% CI = 0.43-0.82; pinteraction = 0.02). Findings for OS were in line with BCSS results. PS-weighting analysis confirmed the results of the primary analysis. CONCLUSIONS: Adjuvant chemotherapy is associated with better BCSS and OS in pT1N0M0 TNBC. Better outcome is most evident in pT1c tumours and may not outweigh harm in pT1a/pT1b tumours.

Prognostic Value of Residual Disease after Neoadjuvant Therapy in HER2-Positive Breast Cancer Evaluated by Residual Cancer Burden, Neoadjuvant Response Index, and Neo-Bioscore.

PURPOSE: In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore. EXPERIMENTAL DESIGN: We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary. RESULTS: A total of 283 women were included. Median follow-up was 67 months (interquartile range 44-100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88-97); patients without pCR had a 5-year RFI of 80% (95% CI, 72-88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR. CONCLUSIONS: The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0-1) after NST who have similar 5-year RFI compared with patients with pCR.

Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. METHODS: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. FINDINGS: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. INTERPRETATION: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. FUNDING: Roche Netherlands.

Neoadjuvant Therapy for Breast Cancer: Established Concepts and Emerging Strategies.

In the last decade, the systemic treatment approach for patients with early breast cancer has partly shifted from adjuvant treatment to neoadjuvant treatment. Systemic treatment administration started as a 'one size fits all' approach but is currently customized according to each breast cancer subtype. Systemic treatment in a neoadjuvant setting is at least as effective as in an adjuvant setting and has several additional advantages. First, it enables response monitoring and provides prognostic information; second, it downstages the tumor, allowing for less extensive surgery, improved cosmetic outcomes, and reduced postoperative complications such as lymphedema; and third, it enables early development of new treatment strategies by using pathological complete remission as a surrogate outcome of event-free and overall survival. In this review we give an overview of the current standard of neoadjuvant systemic treatment strategies for the three main subtypes of breast cancer: hormone receptor-positive, triple-negative, and human epidermal growth factor receptor 2-positive. Additionally, we summarize drugs that are under investigation for use in the neoadjuvant setting.

Additional value of 18F-FDG PET/CT response evaluation in axillary nodes during neoadjuvant therapy for triple-negative and HER2-positive breast cancer.

BACKGROUND: 18F-FDG PET/CT can monitor metabolic activity in early breast cancer during neoadjuvant systemic therapy (NST), but it is unknown if the metabolic breast and axillary response differ. We evaluated the correlation between metabolic breast and axillary response at various time points during NST. Furthermore, we analysed if the combined metabolic response improves pathologic complete response (pCR) prediction compared to using the metabolic breast response alone. METHODS: 18F-FDG PET/CT was performed at baseline (PET1), 2-3 weeks (PET2), and 6-8 weeks (PET3) of NST in patients with triple-negative (TN) and HER2-positive node-positive breast cancer. SUVmax and ∆SUVmax were determined separately for breast and axilla. Spearman's correlation coefficients (r) between both localisations were calculated. The accuracy of pCR total (ypT0/is,ypN0) prediction using the metabolic response in breast, axilla or both was examined using logistic regression analysis. RESULTS: Hundred-five patients were included: 45 TN and 60 HER2-positive tumours. The metabolic response in breast and axilla correlated moderately in TN tumours (r = 0.57) using ∆SUVmax between PET1-PET3 and poorly in HER2-positive tumours (r = 0.49) using SUVmax at PET2. In TN tumours, metabolic breast response predicted pCR well without improvement after adding axillary response (c-index 0.82 versus 0.85, p = 0.63). In HER2-positive tumours, metabolic breast response predicted pCR poorly with improvement after adding axillary response (c-index 0.64 versus 0.72, p = 0.06). CONCLUSIONS: 18F-FDG PET/CT response during NST differs between breast and axilla. In TN tumours, pCR total prediction can be made independent of metabolic axillary response. In HER2-positive tumours, axillary response may improve pCR total prediction. These findings may help guide PET/CT-response-based changes during NST. TRIAL REGISTRATION: NTR NTR1797 . Registered 29 May 2009, retrospectively registered.

MRI predicts pathologic complete response in HER2-positive breast cancer after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant treatment of HER2-positive breast cancer frequently leads to a pathologic complete response (pCR), which is associated with favourable long-term outcome. Treatment regimens typically consist of 6-9 cycles of trastuzumab-based chemotherapy, although many patients achieve early radiologic complete response (rCR). If rCR accurately predicts pCR, the number of chemotherapy cycles can possibly be reduced. METHODS: We performed a diagnostic accuracy study to determine the association between rCR and pCR in patients with stage II-III HER2-positive breast cancer treated with neoadjuvant trastuzumab-based chemotherapy at the Netherlands Cancer Institute. RCR was defined as the disappearance of pathologic contrast enhancement in the original tumour region on repeated magnetic resonance imaging (MRI). PCR was defined as the absence of invasive tumour cells in the resected breast specimen (ypT0/is). Diagnostic accuracy was estimated in the overall population and in subgroups based on hormone receptor (HR) status. The prognostic value of rCR for recurrence-free interval was evaluated as an exploratory analysis. RESULTS: We identified 296 eligible patients with 297 HER2-positive tumours (154 HR-negative and 143 HR-positive) treated with neoadjuvant trastuzumab-based chemotherapy between 2004 and 2016. Overall, the rCR rate was 69% (206/297) and the pCR rate was 61% (181/297). Among 206 patients with rCR, 150 also had pCR (negative predictive value [NPV] = 150/206 = 73%). Among 91 patients without rCR, 60 had residual tumour at pathology (positive predictive value [PPV] = 60/91 = 66%). The NPV was better in HR-negative compared to HR-positive tumours (88 vs. 57%), while the PPV was better in HR-positive tumours (50 vs. 78%). Achieving rCR was associated with a 5-year recurrence-free interval of 88% compared to 68% without rCR (hazard ratio 0.34, 95% confidence interval 0.17-0.65, P = 0.001). CONCLUSION: Achieving rCR corresponds well with pCR in HER2-positive breast cancer, particularly in the HR-negative subgroup. RCR is also associated with improved long-term outcome.

Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study.

AIM: To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. PATIENTS AND METHODS: Patients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m2), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml-1 min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. RESULTS: One hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33-52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82-94), and the 3-year overall survival was 92% (95% CI: 88-98). The most common grade 3-4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. CONCLUSION: An anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.

Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study.

BACKGROUND: The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC). METHODS: The TRAIN-2 study is a neoadjuvant randomized controlled trial in stage II and III HER2-positive breast cancer (NCT01996267). Patients are randomly assigned to receive either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab, followed by six cycles of PTC plus pertuzumab in both arms. Toxicities are described per treatment arm according to the Common Toxicity Criteria for Adverse Events version 4.03. RESULTS: This analysis includes 110 patients balanced over both treatment arms. Neutropenia was the most common hematologic toxicity, with grade 3-4 occurring in 53% in the FEC-T-arm and in 51% in the PTC-arm. Febrile neutropenia occurred in 9% in the FEC-T arm and did not occur in the PTC-arm. Secondary G-CSF prophylaxis was used in 35-40% of patients. Asymptomatic ejection fraction decrease grade 2 was observed in 24% in the FEC-T-arm and 11% in the PTC-arm. The most common grade 3-4 non-hematologic toxicity was diarrhea (5% in the FEC-T-arm and 18% in the PTC-arm). CONCLUSIONS: Pertuzumab in combination with FEC-T mostly causes neutropenia, and when added to PTC mostly causes diarrhea. Significant cardiac toxicity is rare with both regimens, and toxicity is overall well manageable.

The effect of trastuzumab-based chemotherapy in small node-negative HER2-positive breast cancer.

The prognosis of patients with stage II-III Human Epidermal growth factor Receptor 2 (HER2)-positive breast cancer has significantly improved since the addition of trastuzumab to (neo-)adjuvant chemotherapy. Several reports have shown that small (≤2 cm), node-negative, HER2-positive tumors have a relatively poor prognosis and these patients increasingly receive trastuzumab-based chemotherapy. We aimed to provide evidence for this approach in a population-based cohort. All T1N0M0 HER2-positive breast cancer patients diagnosed between 2006 and 2012 were identified from the Netherlands Cancer Registry. Patient, tumor, and treatment characteristics were recorded. Kaplan-Meier statistics were used for overall survival (OS) and breast cancer-specific survival (BCSS) estimations overall and in T1a, T1b, and T1c tumors separately. Cox regression analyses were performed to account for imbalances in baseline characteristics between treated and untreated patients. A total of 3512 patients were identified: 385 with T1a, 800 with T1b, and 2327 with T1c tumors. Forty-five percent of patients received chemotherapy and/or trastuzumab: 92 % received both. Chemotherapy and/or trastuzumab significantly improved 8-year OS (95 vs. 84 %; hazard ratio [HR] 0.29; 95 % confidence interval [CI] 0.21-0.41, P < 0.001). The effect remained significant in multivariable analyses (HR 0.35; 95 % CI 0.23-0.52, P < 0.001). BCSS was also improved with systemic treatment in univariable (96 vs. 92 %; HR 0.41; 95 % CI 0.27-0.63, P < 0.001) and multivariable analyses (HR 0.31; 95 % CI 0.19-0.53, P < 0.001). Treatment effect on OS and BCSS was similar in T1a, T1b, and T1c tumors. Chemotherapy and/or trastuzumab improves OS and BCSS and can be considered in all patients with small node-negative HER2-positive breast cancer.

Clinical assessment of peripheral neuropathy in HIV-infected children on antiretroviral therapy in rural South Africa.

UNLABELLED: Peripheral neuropathy is a well-known side effect of antiretroviral therapy (ART) in adult patients and is particularly related to the use of nucleoside reverse transcriptase inhibitors. This class of drugs is included in all first-line paediatric ART regimens in Africa, but data on the prevalence of neuropathy in children are scarce. In this cross-sectional study, 182 HIV-infected children on ART in rural South Africa were assessed for peripheral neuropathy using the neuropathy symptom score (NSS) and neuropathy disability score (NDS). Peripheral neuropathy was defined as NSS ≥ 5 or NDS ≥ 3. Neurological assessment was completed for 174 children (96 %). Symptoms of neuropathy were reported in NSS by 48 children (28 %; 95 % confidence interval (CI) 21-34 %), and signs were observed in NDS in 25 children (14 %; 95 % CI 12-16 %). A diagnosis of peripheral neuropathy was established in 42 children (24 %; 95 % CI 18-30 %). Independent risk factors for peripheral neuropathy were co-trimoxazole prophylaxis (adjusted odds ratio 0.45; 95 % CI 0.21-0.95, p = 0.036) and didanosine use (adjusted odds ratio 12; 95 % CI 1.3-116, p = 0.030). CONCLUSION: Peripheral neuropathy as determined by clinical assessment is a common condition in African children on ART.

Blood lactate in HIV-infected children on antiretroviral therapy in rural South Africa.

We studied blood lactate levels in 253 South African children on antiretroviral therapy. The prevalence of hyperlactatemia was 68% and severity was mild in most cases (69%). There was no association of symptoms and/or signs with hyperlactatemia. Independent predictors were lipo-dystrophy, time on antiretroviral therapy and baseline CD4 count. Increased awareness of hyperlactatemia in African children on antiretroviral therapy is warranted.

Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report.

BACKGROUND: Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use. CASE PRESENTATION: A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved. CONCLUSIONS: Efavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child.