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Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC 50 ) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1β) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G 1 phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC., Methods: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR)., Results: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients., Conclusion: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence., (© 2024. The Author(s).)

Background: Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owing to its potential to enhance the life quality of patients., Methods and Results: The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice., Conclusion: (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Dian et al.)

Background: TCbHP (taxane + carboplatin + trastuzumab + pertuzumab) is the preferred neoadjuvant therapy regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no consensus exists regarding whether specific populations may be exempt from carboplatin, allowing for de-escalation to the THP (taxane + trastuzumab + pertuzumab) regimen. Additionally, the optimal number of cycles for neoadjuvant THP remains unclear. We compared the efficacy and safety of neoadjuvant TCbHP and THP regimens, providing clinicians with a nuanced perspective to guide their treatment regimen selection., Methods: This multicenter real-world study included patients with HER2-positive breast cancer undergoing neoadjuvant TCbHP or THP between March 2019 and February 2023. Efficacy was assessed through the pathological complete response (pCR) rate, while safety was evaluated through monitoring adverse events., Results: Among 220 patients, 103 received 6 cycles of TCbHP (TCbHP×6), 83 received 6 cycles of THP (THP×6), and 34 received 4 cycles of THP (THP×4). The TCbHP×6 cohort exhibited a 66% pCR rate compared with 53% in the THP×6 cohort (P = 0.072). Subgroup analysis revealed that in patients aged ≤ 50 years, those with hormone receptor (HR)-negative status, and those with clinical stage T2, the pCR rate of the TCbHP×6 regimen was significantly higher than the THP×6 regimen (P < 0.05). The TCbHP×6 cohort reported higher frequencies of any-grade adverse events (99% versus 86.7%) and grade 3-4 events (49.5% versus 12%) than the THP×6 cohort. Propensity score matching identified 27 patient pairs between the THP×6 and THP×4 cohorts, indicating a significantly higher pCR rate for the THP×6 regimen than the THP×4 regimen (63% versus 29.6%, P = 0.029)., Conclusions: The TCbHP×6 regimen is favored for individuals aged ≤ 50 years and those aged > 50, ≤60 years with HR-negative status or clinical stage T2-4. For patients in compromised general condition or lacking the specified indications, the THP×6 regimen emerges as a lower-toxicity alternative with satisfactory efficacy. To ensure treatment efficacy, a minimum of 6 cycles of neoadjuvant THP is required., (© 2024. The Author(s).)

Purpose: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer., Methods: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity., Results: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02)., Conclusion: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.

Background: Inetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated., Methods: This prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints., Results: Forty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs., Conclusion: Neoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment., Trial Registration: NCT05749016 (registration date: Nov 01, 2021)., (© 2024. The Author(s).)

Purpose: Anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy is effective for perioperative breast cancer treatment. However, these treatments frequently induce oral mucositis (OM), with an incidence ranging from 20 to 50%. The association of OM development between different chemotherapeutic treatments remains unclear. Consequently, this study aimed to compare OM development during docetaxel-containing chemotherapy between patients with and without OM experience during previous anthracycline-cyclophosphamide treatments to assess the association between OM development and treatment regimens., Methods: Seventy-two patients with breast cancer receiving anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy as a perioperative treatment were categorized into the control (no prior OM experience with anthracycline-cyclophosphamide) and OM-experience (OM development during previous treatment) groups and retrospectively evaluated. The primary endpoint was the incidence of all-grade OM in the first docetaxel-containing chemotherapy cycle. Additionally, the incidences of OM and dysgeusia during all treatment cycles and factors associated with the incidence of OM were evaluated., Results: The incidence of all-grade OM in the first cycle was significantly higher in the OM-experience group (54.2%) than in the control group (10.4%; P < 0.0001). Furthermore, its incidence in all treatment cycles was higher in the OM-experience group (66.7%) than in the control group (12.5%, P < 0.0001). However, the incidence of dysgeusia did not differ between the groups. Multivariate logistic regression analysis revealed OM experience during previous anthracycline-cyclophosphamide treatment and concomitant pertuzumab use as independent risk factors for OM development in subsequent docetaxel-containing chemotherapy., Conclusion: Our study suggests that patients experiencing OM with anthracycline-cyclophosphamide during perioperative breast cancer treatment exhibit symptoms following subsequent docetaxel-containing chemotherapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer., Patients and Methods: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN., Results: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects., Conclusion: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: We previously reported that S-1 and low-dose docetaxel (DOC) (N-1 study, phase II trial) could be a well-tolerated and effective neoadjuvant chemotherapies (NACs) for patients with operable breast cancer. Herein, we analyzed the long-term outcomes and developed clinicopathological and molecular predictors of pathological complete response (pCR)., Patients and Methods: Eighty-three patients received S-1 (40 mg/m 2 orally on days 1-14) and DOC (40 mg/m 2 intravenously on day 1) every 3 weeks for 4 to 8 cycles. Disease-free survival (DFS) and overall survival (OS) were analyzed for each population with a pCR status. To assess the relationship between pCR and clinicopathological factors such as tumor-infiltrating lymphocytes (TILs, 1+ <10%, 2+ 10%-50%, and 3+ >50%) and nuclear grade (NG), microarray was used to compare the microRNA profiles of the pCR and non-pCR groups using core needle biopsy specimens., Results: With a median follow-up duration of 99.0 (range, 9.0-129.0) months, the 5-year DFS and OS rates were 80.7% and 90.9%, respectively. The 5-year OS rate of the pCR group was significantly better than that of the non-pCR group (100% vs. 86.2%, p = .0176). Specifically, in triple-negative patients, the difference was significant (100% vs. 60.0%, p = .0224). Multivariate analysis revealed that high TILs (≥2-3+) and NG 2-3 independently predicted pCR. Microarray data revealed that 3 miRNAs (miR-215-5p, miR-196a-5p, and miR-196b-5p) were significantly upregulated in the pCR group., Conclusion: Our NAC regimen achieved favorable long-term outcomes and significantly improved OS in the pCR group. High TILs, NG 2-3, and some miRNAs may be predictors of pCR., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre., Methods: This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery., Results: Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery., Conclusion: This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: HER2 positive disease accounts for 15-20% of early breast cancer. Achieving a pathological complete response after neoadjuvant chemotherapy (NACT) improves prognosis and decreases risk of recurrence., Case Report: Our case report aimed to highlight an emblematic clinical success and benefit of NACT with the addition of pertuzumab to the standard trastuzumab/taxane/anthracycline combination in a patient with a 9 cm breast neoplasm and extensive lymph node involvement (>4 pathological lymph nodes)., Conclusion: Achieving a complete pathological response with NACT, should be the main goal, especially in patients with triple negative and HER2 positive breast cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

With the increasing number of young breast cancer (BC) patients worldwide, concerns about hair loss and skin change persist among BC survivors. This study aimed to evaluate the hair loss and skin changes in Asian BC patients and to compare them according to the treatment regimens. This study enrolled 322 patients scheduled to undergo BC surgery. Hair loss and skin changes were assessed at the following two time points: one day before surgery and 6 months after surgery. Patients who had received systemic anticancer treatment before surgery were assigned to the neoadjuvant treatment group, while patients who were scheduled to receive systemic anticancer treatment were assigned to the adjuvant treatment group. In the adjuvant treatment group, patients with taxane-based chemotherapy had significantly higher odds of increased hair loss, a higher melanin index, and an increased volume of wrinkles (p < 0.0001, p = 0.0110, and p = 0.0371, respectively). In the neoadjuvant treatment group, hair loss was reversed in most patients at 6 months after surgery. Clinicians should inform BC patients about the potential for hair loss and skin changes and provide supportive care to mitigate the effects on the patients' quality of life., (© 2024 Japanese Dermatological Association.)

Purpose: The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study., Methods: Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0-9), intermediate (10-49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher's exact test., Results: Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002-0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2 H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001-0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses., Conclusion: These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support this practice. This is a retrospective, multicenter study. A total of 142 patients were included in the study who are HER2-positive breast cancer, aged ≤ 65 years, with left ventricular ejection fraction ≥ 50%, received neoadjuvant chemotherapy and underwent surgery at 10 different oncology centers in Türkiye between October 2016 and December 2022. The treatment arms were divided into 4-6 cycles of docetaxel/trastuzumab/pertuzumab for arm A, 4 cycles of adriamycin/cyclophosphamide followed by 4 cycles of taxane/TP for arm B. There were 50 patients (35.2%) in arm A and 92 patients (64.8%) in arm B. The median follow-up of all of the patients was 19.9 months (95% CI 17.5-22.3). The 3-year DFS rates for treatment arms A and B were 90.0% and 83.8%, respectively, and the survival outcomes between the groups were similar (p = 0.34). Furthermore, the pathologic complete response rates were similar in both treatment arms, at 50.0% and 51.1%, respectively (p = 0.90). This study supports shortened neoadjuvant treatment of HER2-positive breast cancer, a common practice in some clinics., (© 2024. The Author(s).)

Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy., Methods: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual., Results: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51)., Conclusion: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments., (© 2024. The Author(s).)

Background: This prospective real-world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China., Patients and Methods: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo-/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m 2 ) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed., Results: One hundred and thirty-four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3-15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first- or second-line treatment was significantly better than those who received eribulin as ≥3-line treatment (6.9 months [95% CI: 3.2-8.8] vs. 4.0 months [95% CI: 3.4-4.6], p = 0.006). The mPFS of patients with triple-negative, HER2-positive, and HER2(-)/HR(+) was 3.4 (95% CI: 2.7-4.1), 6.2 (95% CI: 2.3-10.1) and 5.0 months (95% CI: 4.1-5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6-6.3] vs. 4.0 months [95% CI: 3.3-4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non-TNBC receiving eribulin as ≤2-line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment-related adverse events., Conclusion: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real-world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy., Methods: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models., Results: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology., Conclusion: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy., (© 2022. The Author(s).)

Background: Neoadjuvant chemotherapy before mastectomy helps reduce tumor burden and pathologic response in breast cancer. Limited evidence exists regarding how neoadjuvant chemotherapy impacts outcomes following microvascular breast reconstruction. This study examines the effects of neoadjuvant chemotherapy regimens and schedules on microvascular breast reconstruction complication rates and also assesses the effects of neoadjuvant chemotherapy on circulating immune cells related to wound healing., Methods: Patients who underwent neoadjuvant chemotherapy and microvascular breast reconstruction at Yale New Haven Hospital between 2013 and 2018 were identified. Demographic variables, oncologic history, chemotherapy regimens, and complication profiles were collected. Chemotherapy regimens were stratified by inclusion of anthracycline and order of taxane administration. Chi-square, Fisher's exact, and t tests were used for univariate analysis. Multivariate binary logistic regression was used to control for covariates., Results: One hundred patients met inclusion criteria. On multivariate analysis, the administration of taxane first in an anthracycline-containing chemotherapy sequence was associated with increased complications (OR, 3.521; p = 0.012), particularly fat necrosis (OR, 2.481; p = 0.040). In the logistic regression model evaluating the effect of the taxane-first regimen on complication rates, the area under the curve was estimated to be 0.760 (p < 0.0001), particularly fat necrosis 0.635 (p < 0.05). The dosage of chemotherapy, number of days between neoadjuvant chemotherapy completion and surgery, and number of circulating immune cells did not significantly differ among patients who experienced complications., Conclusions: Taxane-first, anthracycline-containing neoadjuvant chemotherapy regimens were associated with increased complications, particularly fat necrosis. The increased postreconstruction complication risk must be weighed against the benefits of taxane-first regimens in improving tumor outcome., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Objective: This study aimed to investigate level fluctuations of serum biomarkers that are associated with cardiotoxicity risk, such as high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein-B (Apo-B) in response to chemotherapy treatment for breast cancer., Method: The serum levels of hs-CRP and Apo-B were evaluated in 56 breast cancer patients with main inclusion criteria: HER2 negative and who received adjuvant chemotherapy AC [A: Adriamycin, C: Cyclophosphamide] or AC→T [A: Adriamycin, C: Cyclophosphamide, T: Taxane] regimes at early II (n = 26) and late IV (n = 30) clinical stages by using particle enhanced turbidimetric assay., Results: The results of this study suggest that a high level of pre-treatment hs-CRP is a good prognostic marker in comparison to Apo-B. Moreover, the AC-T chemotherapy regime treatment in both early and late stages exhibited a significantly higher level of hs-CRP compared to that in the AC regime. Hs-CRP was significantly elevated in the early stage in comparison to the late stage among cancer patients, meanwhile Apo-B behaved inversely. Furthermore, the results showed that hs-CRP levels were significantly higher in late-stage cancer patients compared with those in early-stage in both chemotherapy regimens groups. On the other hand, Apo-B showed no significant differences., Conclusion: Monitoring hs-CRP level changes in comparison to Apo-B can be used to assist the side effect risk difference among different chemotherapy regimens, and staging reflecting a positive correlation between them more notable in the late stage.

Background: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting., Methods: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out., Results: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062)., Conclusions: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer., Clinical Trial Registration: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Targeted drug delivery for cancer therapy is an emerging area of research. Cancer cells overexpress certain biomarkers that can be exploited for their targeted therapy. Cyclic cell-penetrating peptides (cCPP) are increasingly assessed for intracellular cargo delivery in cancer cells. In this study, we have conjugated cabazitaxel (CBT) to the cCPP via an ester bond to assist CBT release in the tumor's acidic environment. Integrin targeting (RGDC, TP1) and extra domain B of fibronectin (EDB-Fn) targeting (CTVRTSAD, TP2) peptides were linked to the peptide-drug conjugate (cCPP-CBT) via a disulfide bond to provide targeting ability to the conjugates until they reach the tumor site. Conjugate 11 (TP1-cCPP-CBT) and conjugate 16 (TP2-cCPP-CBT) showed approximately 3-4-fold less antiproliferative activity on integrin and EDB-FN overexpressing cancer cell lines as compared to the CBT analogue used for comparison (CBT-GA, 5 ). Conjugates ( 11 and 16 ) were less toxic (31-34-fold less antiproliferative activity) to the normal human embryonic kidney (HEK-293) cells as compared to CBT. The flow cytometry and quantitative confocal microscopy data further confirm the selective efficacy of conjugates (TP1-cCPP-FAM ( 10 ) and TP1-cCPP-FAM ( 15 )) toward biomarker overexpressing cancer cells. Furthermore, the stability and release studies of conjugate 11 revealed its therapeutic potential under different conditions, such as human plasma, different pHs, and redox conditions. This conjugation strategy was proven to enhance chemotherapeutics agents' efficacy and targeting and can be applied to other chemotherapeutic agents.

Background: Pathologic complete response (pCR) has been shown to be associated with favorable outcomes in breast cancer. Predictors of pCR could be useful in guiding treatment decisions regarding neoadjuvant therapy. The objective of this study was to evaluate cyclin E as a predictor of response to neoadjuvant chemotherapy in breast cancer., Methods: Patients (n = 285) with stage II-III breast cancer were enrolled in a prospective study and received neoadjuvant chemotherapy with anthracyclines, taxanes, or combination of the two. Pretreatment biopsies from 190 patients and surgical specimens following chemotherapy from 192 patients were available for immunohistochemical analysis. Clinical and pathologic responses were recorded and associated with presence of tumor infiltrating lymphocytes, cyclin E, adipophilin, programmed cell death-ligand 1, and elastase staining and other patient, tumor and treatment characteristics., Results: The pCR rate was significantly lower in patients with cytoplasmic cyclin E staining compared with those who had no cyclin E expression (16.1% vs 38.9%, P = 0.0005). In multivariable logistic regression analysis, the odds of pCR for patients who had cytoplasmic negative tumors was 9.35 times (P value < 0.0001) that compared with patients with cytoplasmic positive tumors after adjusting for ER, PR, and HER2 status. Cytoplasmic cyclin E expression also predicts long-term outcome and is associated with reduced disease free, recurrence free, and overall survival rates, independent of increased pretreatment tumor infiltrating lymphocytes., Conclusions: Cyclin E independently predicted response to neoadjuvant chemotherapy. Hence, its routine immunohistochemical analysis could be used clinically to identify those breast cancer patients expected to have a poor response to anthracycline/taxane-based chemotherapy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Multi-gene prognostic signatures of long non-coding RNAs (lncRNAs) provide new insights into mechanisms of HER2-negative breast cancer development and progression, and predict distant relapse-free survival (DRFS) of patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. The aim of this study was to develop such a multi-lncRNAs signature. Optimal multiple candidate signature lncRNAs associated with DRFS were firstly identified by a univariate Cox proportional hazard regression survival analysis and a robust likelihood-based survival analysis of the GEO dataset GSE25055. A nine-lncRNA prognostic risk score model Risk Score = 0.0289 × EXP LOC100507388 - 0.0814 × EXP LINC00094 - 0.2422 × EXP SMG7-AS1 - 0.2433 × EXP PP14571  + 0.4690 × EXP ASAP1-IT1 - 0.2483 × EXP LOC103344931 - 0.2464 × EXP FAM182A  + 0.3349 × EXP HCG26 - 0.0216 × EXP LINC00963 was built according to the coefficients of multivariate survival analysis of the association between the candidate lncRNAs and survival. EXP lncRNA was the standardized log2-transformed expression level of the gene. According to this model, higher scores predicted lower survival probability. The area under Receiver operating characteristic (ROC) curve (AUC) was 0.777 to 0.823 from 1- to 7- year survival rate. The model and its individual lncRNAs differentiated survival probability between the higher scores (expression) and the lower scores (expression). The nine-lncRNA signature had the robust prognostic power compared with ER, PR, tumor size (T), lymph node invasion (N), TNM stage, pathologic response, chemosensitivity prediction and PAM50 signature. These results were consistent with those based on the GEO dataset GSE25065. The predictive nomograms integrating both the nine-lncRNA signature classifier and clinical-pathological risk factors were robust in predicting 1-, 3- and 5- year survival probabilities. These results supported that the nine-lncRNA signature was a robust and effective model in predicting DRFS of patients with HER2-negative breast cancer following taxane and anthracycline-based neoadjuvant chemotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age., Methods: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing., Findings: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1])., Interpretation: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy., Funding: European Commission Sixth Framework Programme., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and solvent-based taxanes (sb-taxanes) as neoadjuvant therapy in the treatment of breast cancer., Methods: We systematically searched the PubMed, Embase, and Cochrane Central Register databases. Randomized controlled trials (RCTs) and cohort studies, published in English, about the comparison between nab-paclitaxel and sb-taxanes as neoadjuvant therapy in patients with breast cancer were searched up to September 2019., Results: The primary outcome was the proportion of patients with pathological complete response (pCR, defined as ypT0 ypN0 or ypT0/is ypN0). Other main outcomes included long-term survival and adverse events (AEs). Seven studies (five RCTs and two cohorts) and 2949 patients were included. Neoadjuvant nab-paclitaxel improved pCR compared with sb-taxanes (ypT0 ypN0: OR = 1.52, 95%CI: 1.27-1.83, P < 0.001; ypT0/is ypN0: OR = 1.40, 95%CI: 1.17-1.68, P < 0.001). The benefits of nab-paclitaxel on pCR were persistent in HER2-negative, hormone receptor (HR)-positive breast cancer (OR = 1.53, 95%CI: 1.07-2.19, P = 0.020), triple-negative breast cancer (weekly/every 2 weeks regimen; OR = 2.95, 95%CI: 1.54-5.67, P < 0.001), and tumors with Ki-67 > 20% (OR = 1.63, 95%CI: 1.26-2.12, P < 0.001). Patients treated with nab-paclitaxel had better event-free survival (EFS; HR = 0.69, 95%CI: 0.57-0.85, P < 0.001) than with sb-taxanes. There were no differences in most of grade > 3 AEs between nab-paclitaxel and sb-taxanes (all P > 0.05), besides of any grade hypersensitivity (OR = 0.29, 95%CI: 0.11-0.72, P = 0.008), any grade (OR = 2.10, 95%CI: 1.37-3.23, P = 0.001) and grade > 3 (OR = 4.01, 95%CI: 2.51-6.41, P < 0.001) neuropathy., Conclusion: Nab-paclitaxel is effective for the treatment of non-metastatic breast cancer in the neoadjuvant setting. Nab-paclitaxel could improve pCR rate and EFS compared with sb-taxanes and with reasonable toxicities.

Objective: Chromosomal instability (CIN) is a hallmark of cancer characterized by cell-to-cell variability in the number or structure of chromosomes, frequently observed in cancer cell populations and is associated with poor prognosis, metastasis, and therapeutic resistance. Breast cancer (BC) is characterized by unstable karyotypes and recent reports have indicated that CIN may influence the response of BC to chemotherapy regimens. However, paradoxical associations between extreme CIN and improved outcome have been observed., Methods: This study aimed to 1) evaluate CIN levels and clonal heterogeneity (CH) in MCF7, ZR-751, MDA-MB468, BT474, and KPL4 BC cells treated with low doses of tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), Herceptin (HT), and combined treatments (TAM/DOC, TAM/DOX, TAM/HT, HT/DOC, and HT/DOX) by using fluorescence in situ hybridization (FISH), and 2) examine the association with response to treatments by comparing FISH results with cell proliferation., Results: Intermediate CIN was linked to drug sensitivity according to three characteristics: estrogen receptor α (ERα) and HER2 status, pre-existing CIN level in cancer cells, and the CIN induced by the treatments. ERα+/HER2 - cells with intermediate CIN were sensitive to treatment with taxanes (DOC) and anthracyclines (DOX), while ERα - /HER2 - , ERα+/HER2+, and ERα-/HER2+ cells with intermediate CIN were resistant to these treatments., Conclusions: A greater understanding of CIN and CH in BC could assist in the optimization of existing therapeutic regimens and/or in supporting new strategies to improve cancer outcomes., (Copyright: © 2020, Cancer Biology & Medicine.)

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer., Methods: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data., Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1)., Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting., Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this study, we detected and measured the count of circulating tumour cells (CTCs) in breast cancer (BC) patients who were treated by neoadjuvant chemotherapy (NAC) in order to assess the clinical validity of CTCs. A total of 96 patients with locally advanced BC and who were treated by NAC were enrolled in this study. The CTC count in the peripheral blood was estimated by negative enrichment-fluorescence in situ hybridization before and after NAC. The clinicopathological data of the patients were recorded. CTCs were detected in 59 of the 96 patients with BC before NAC. Particularly, the detection rate of CTCs was significantly lower in human epidermal growth factor receptor-2 (HER-2)-negative patients than in HER-2-positive patients. CTCs were significantly fewer after NAC than before NAC. The CTC-detection sensitivity in the NAC efficacy evaluation was 75.5% (40/53), while the specificity was 72.1% (31/43). The CTC consistency analysis with clinical effects (Response Evaluation Criteria in Solid Tumors Version 1.1 Standard) was described as moderate (kappa = 0.476, P  < 0.001). Thus, our findings suggest that CTC detection is a potential new approach to assess the efficacy of NAC.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial., Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents., Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019., Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide., Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS., Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS., Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study., Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Purpose: Taxane-induced peripheral neuropathy (TIPN) is a common and bothersome toxicity. This study aimed to determine the incidence and severity of TIPN in patients with breast cancer and to investigate the relationship between TIPN and quality of life., Methods: A total of 82 breast cancer patients with TIPN symptoms were included in this study. The criteria of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30, version 3.0) were used to evaluate grading of sensory neuropathy and quality of life, respectively. Analysis of the data was done by IBM SPSS statistics version 23., Results: A total of 346 patients received taxane-based chemotherapy and 82 patients (23.7%) experience TIPN. The mean (SD) global health status/quality of life, physical functioning, role functioning, and pain subscales were 60.63 (5.26), 80.64 (9.05), 81.77 (10.41), and 43.88 (11.27), respectively. There were significant negative correlations between global health status/quality of life, physical functioning, and role functioning subscales with the grade of neuropathy (r = -0.33, -0.80, and -0.61, respectively) and positive correlation between pain subscale and the grade of neuropathy (r = 0.70)., Conclusion: This study shows a clear association between TIPN and worsened quality of life. These findings emphasize on detecting and management of TIPN in an effort to improve the quality of life of breast cancer patients.

The aims of this study were to investigate the impact of the relative dose intensity (RDI) of chemotherapy on disease-free survival (DFS) and overall survival (OS), to identify the optimal RDI cut-off points with the docetaxel, epirubicin and cyclophosphamide (TEC) regimen for stage I-III breast cancer patients and to explore the adverse events in these patients. To achieve this, we performed a retrospective analysis of breast cancer patients treated at the First Affiliated Hospital of Chongqing Medical University in 2011. The results showed that among 293 patients with the TEC regimen, 85% and 80% were the cut-off points at which a high RDI was associated with better overall survival (HR = 2.04; 95% CI 1.13, 3.70; p = 0.02) and disease-free survival (HR = 1.97; 95% CI 1.14-3.42; p = 0.02), respectively. Among 169 HR(+) patients, 80% was the cut-off point for DFS (HR = 2.33; 95% CI 1.07-5.08; p = 0.03), and 85% was the cut-off point for OS (HR = 3.00; 95% CI 1.24-7.26; p = 0.02). Among 105 HR(-) patients, 80% was the cut-off point for OS (HR = 2.86; 95% CI 1.05-7.80; p = 0.04). Of 293 patients, neutropenia, nausea, and vomiting were found to be correlated with the level of RDI. In conclusion, a higher RDI of chemotherapy is associated with better survival but with a higher probability of causing adverse events. To optimize survival benefits, the RDI should be maintained ≥ 85% for HR(+) patients and ≥ 80% for HR(-) patients.

Background: Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes., Methods: The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR)., Results: Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2-4.4) and 15.2 months (95% CI 11.3-19.4), respectively. Regarding toxicity, grade 3-4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment., Conclusions: This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.

Purpose: Due to advances in anticancer treatment and supportive care, patients increasingly complained about nonphysical side effects of chemotherapy and targeted therapy in recent years. Therefore, continuous assessment of side effects and patients' perceptions is important. The aim of this study was to evaluate the identification and severity of side effects perceived by ovarian cancer (OC) and breast cancer (BC) patients undergoing contemporary anticancer therapy., Methods: Between 2015 and 2017, consecutive chemo-naïve OC and BC patients were enrolled in this prospective cohort study. Interviews were performed 12 ± 3 weeks after start of anticancer therapy, and patients were asked to select and rank, according to severity, 72 physical or nonphysical symptoms potentially related to their treatment. Data were analyzed with descriptive statistics., Results: Forty-five OC patients and 98 BC patients completed the interview. Sleeping difficulties were ranked as the most troublesome symptom, followed by concerns about family or partner, and loss of hair. Alopecia was the most predominant side effect for BC patients, whereas OC patients were highly afflicted by numbness in limbs. Chemotherapy alone or in combination with targeted therapy caused pronounced sleep disturbances. Prolonged taxane treatment led to shortness of breath and numbness in limbs. Vomiting was ranked by one and nausea by eight women among the five most bothersome symptoms., Conclusions: Sleep disturbances have lately emerged as the most severe problem in women with OC or BC receiving anticancer therapy. Concerns about family and partner were ranked second in the current study and first in previous investigations.

Background and Objectives: Marking positive lymph nodes (LNs) before neoadjuvant chemotherapy (NAC) may improve the accuracy of sentinel lymph node biopsy (SLNB). The aim of this study was to determine the feasibility of marking LNs with 4% carbon microparticle suspension (CMS) before NAC and to evaluate if this technique would improve the SLNB identification rate., Methods: A prospective study of patients with cT1-T4, cN1-N2 breast cancer who underwent US-guided fine-needle aspiration biopsy (FNAB) of suspected LNs and concomitant marking with 4% CMS was performed. After NAC, LNs marked with 4% CMS and those marked with Patent Blue V dye (PBV) were identified and resected., Results: Of the 123 patients included, 74 (60.1%) had positive LNs at FNAB. During axillary surgery, 4% CMS was identified in 121 of 123 patients (98.3%) and blue sentinel LNs in 91% (112 of 123 patients) (P = .0103). Comparing isolated results of PBV and 4%CMS + PBV, the association was better in identifying positive LNs (72.2% vs 97.7%) (P = .02)., Conclusion: The association of 4% CMS and PBV is feasible and significantly increased the identification rate of positive LNs. 4% CMS may play an important role as a complementary technique in patients submitted to NAC., (© 2020 Wiley Periodicals, Inc.)

Objective: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC)., Methods: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects., Results: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change., Conclusion: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 + mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade., Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 + mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m 2 on days 1 and 8) or taxane (docetaxel 75 mg/m 2 on day 1 or paclitaxel 80 mg/m 2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested., Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 + mBC in Japan., Trial Registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

Purpose: To prospectively compare HRQoL effects of two modern adjuvant chemotherapy breast cancer treatment regimens at six time-points up to 16 months after random assignment., Methods: The open-label, randomized, Phase 3 "Panther trial" was conducted between February 2007 and September 2011. 760 women, aged 65 years and younger, after surgery for non-metastatic node-positive or high-risk node-negative breast cancer were randomized 1:1 to the experimental group (four cycles of tailored and dose-dense adjuvant epirubicin and cyclophosphamide/2 weeks followed by four cycles of tailored dose-dense docetaxel/2 weeks) or standard group (three cycles of fluorouracil and epirubicin-cyclophosphamide/3 weeks followed by three cycles of docetaxel/3 weeks). HRQoL was assessed at all Swedish centres using EORTC QLQ-C30 and EORTC QLQ-BR23 at six points during 16 months before randomization., Results: Response rates to questionnaires were highest at baseline 728/780 (93%) and lowest 16 months after randomization, 557/750 (74%). HRQoL declined during treatment in both groups. At the end of treatment, the experimental group reported statistically significantly lower HRQoL (P < 0.001) than the standard group on global health status, physical functioning, role functioning, social functioning, fatigue, sexual functioning, and systemic therapy effects. No differences were found for emotional functioning, body image, and arm and breast symptoms. There were no statistically significant differences between the groups at the first follow-up and at subsequent assessments. HRQoL levels at the 16-month follow-up were similar to baseline values., Conclusions: Negative HRQoL impact of the dose-dense and tailored strategy appears to be prominent during treatment, but HRQoL recover once treatment ends., Trial Registration: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Purpose: Women with residual invasive breast cancer at the primary site or axillary lymph nodes following neoadjuvant chemotherapy have a high risk of recurrence. Eribulin improves survival in patients with metastatic breast cancer who progress after anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of postoperative eribulin in breast cancer patients who did not achieve a pCR following standard neoadjuvant chemotherapy., Methods: Women with localized breast cancer who had residual invasive cancer following ≥ 4 cycles of standard anthracycline and/or taxane-containing neoadjuvant chemotherapy received adjuvant eribulin treatment. HER2-positive patients also received trastuzumab for 1 year. Adjuvant hormonal therapy and locoregional radiotherapy were administered as per institutional guidelines. Primary endpoint was the 2-year DFS rate. Three patient cohorts were analyzed: TNBC (Cohort A), HR+/HER2- (Cohort B), and HER2+ (Cohort C)., Results: One hundred twenty-six patients (Cohort A-53, Cohort B-42, and Cohort C-31) were enrolled. Neoadjuvant chemotherapy included a taxane and an anthracycline in 70%. Eribulin was well tolerated; 84% of patients received the planned 6 cycles. After a median follow-up of 28 months, the 24-month DFS rates were 56% (95% CI 42, 69), 83% (95% CI 67, 91), and 73% (95% CI 53, 86) for Cohorts A, B, and C, respectively. The most common grade 3/4 treatment-related adverse events were neutropenia (26%), leukopenia (13%), and neuropathy (7%)., Conclusion: Administration of adjuvant eribulin after neoadjuvant chemotherapy was feasible and well tolerated. The 24-month DFS rate did not reach the study target levels in any of the cohorts and was similar to DFS previously described in these cohorts following neoadjuvant chemotherapy alone.

Background: Pertuzumab-based neoadjuvant chemotherapy (NAC) has demonstrated successful pathologic complete response (pCR) rates when administered to patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer and has become standard of care. This study aimed to identify pCR rates in patients receiving a variety of pertuzumab-based NAC regimens. The effect of the addition of an anthracycline and impact of anthracycline and taxane sequencing on pCR was also assessed., Methods: A retrospective, single-center review was conducted on patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer that received one of five pertuzumab-containing NAC regimens followed by definitive surgery., Results: Ninety-six patients were included in the analysis; overall, pCR was attained in 49 patients (51%). Of the 61 patients who received an anthracycline-containing NAC regimen, 30 (49%) attained a pCR. Of the 35 patients who received the non-anthracycline NAC regimen, 19 (54%) attained a pCR; difference in pCR was not statistically significant ( p  = 0.63). Anthracycline/taxane sequence analysis showed that of the patients attaining pCR with an anthracycline-containing NAC, 77% of patients received the taxane portion upfront ( p  = 0.17). Relative dose intensity of the anthracycline portion was similar irrespective of treatment sequence. However, relative dose intensity of the taxane portion was decreased with upfront anthracycline administration., Conclusion: These findings support current recommendations of adding pertuzumab to established regimens for treatment of locally advanced, HER2-positive, early stage breast cancer. The benefit of adding an anthracycline in the neoadjuvant setting remains unclear. Patients treated with the taxane portion of NAC upfront appeared to have a higher rate of pCR and better relative dose intensity than patients who received the anthracycline portion upfront, but differences were not statistically significant. These findings should be verified in a prospective clinical trial.

Purpose: In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC)., Methods: Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints., Results: The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators., Conclusions: The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Paclitaxel is one of the most effective chemotherapy drugs for breast cancer worldwide but 20‑30% patients show primary resistance to the drug. Screening and identification of markers that facilitate effective and rapid prediction of sensitivity to paclitaxel is therefore an urgent medical requirement. In the present study, G protein signaling modulator 2 (GPSM2) mRNA levels were significantly associated with taxane sensitivity in experiments based on the Gene Expression Omnibus (GEO) online database. Immunohistochemical analysis consistently revealed a significant association of GPSM2 protein levels with paclitaxel sensitivity in breast cancer patients. Knockdown of GPSM2 reduced the sensitivity of breast cancer cells to paclitaxel via regulation of the cell cycle. Animal experiments further corroborated our in vitro findings. These results suggest that GPSM2 plays an important role in breast cancer resistance, supporting its utility as a potential target for improving drug susceptibility in patients as well as a marker of paclitaxel sensitivity.

Background and Objective: Taxane-induced peripheral neuropathy (TIPN) is a main toxicity of taxanes with no effective treatment. This study aimed to compare the efficacy and safety of pregabalin (150 mg daily) and duloxetine (60 mg daily) for managing TIPN in breast cancer patients., Methods: This randomized, double-blind, Phase II clinical trial was carried out at a chemotherapy center affiliated to Mazandaran University of Medical Sciences. Patients with breast cancer who received paclitaxel or docetaxel and had a grade 1 or more neuropathy (based on the National Cancer Institute Common Terminology Criteria for Adverse Events version (NCI-CTCAE v4.03), and who had score 4 or higher neuropathic pain severity [based on the visual analog scale (VAS)] were enrolled. Response to treatment was assessed based on improvements in the VAS, NCI-CTCAE, and Patient Neurotoxicity Questionnaire (PNQ) scores during a 6-week trial., Results: Both interventions were effective in decreasing TIPN compared to baseline. At Week 6, the VAS scores were improved in 37/40 (92.5%) and 16/42 (38.1%) of the patients in the pregabalin and duloxetine groups, respectively (p < 0.001). Improvement in NCI-CTCAE sensory neuropathy was also more significant with pregabalin (37/40; 92.5%) in comparison to duloxetine (13/42; 31%) (p < 0.001). Pregabalin was also more beneficial than duloxetine in improving the PNQ scores by 36/40 (90%) and 13/42 (31%), respectively (p < 0.001). Both interventions were tolerated well with mild adverse events., Conclusions: Both pregabalin and duloxetine were well tolerated and efficacious in relieving neuropathic pain, however a 60 mg dose of duloxetine is inferior to a 150 mg dose of pregabalin.

Purpose: We performed a network meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of HER2-targeted agents in combination with taxanes and to identify the best strategy for HER2 + metastatic breast cancer (MBC)., Methods: Pubmed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials that evaluated any taxanes+HER2-targeted agents in the treatment of HER2 + MBC. The primary outcome was overall survival (OS). The secondary outcomes included overall response rate (ORR) and progression-free survival (PFS)., Results: A total of 13 RCTs were eligible, involving 4941 patients and 10 regimens. The result showed that single-HER2-targeted agent+a taxane did improve the effect on ORR and PFS than taxane alone, but only trastuzumab+a taxane had a significant improvement in OS outcomes. Single-HER2-targeted agent (trastuzumab) combined with taxane-based doublets (taxane+carboplatin/capecitabine/doxorubicin/bevacizumab) showed no further benefit than trastuzumab+a taxane. Doublet-HER2-targeted agents combined with a taxane(trastuzumab+pertuzumab+a taxane) showed further improvement in ORR, PFS, and all OS outcomes than single-HER2-targeted agent+a taxane. Ranking analysis based on their P-scores suggested that trastuzumab+pertuzumab+a taxane was the best combination treatment for all the efficacy outcomes., Conclusions: These findings demonstrate that combining two HER2-targeted agents (trastuzumab+pertuzumab) with a taxane is much more beneficial for the treatment of HER2 + MBC. Dual HER2-targeted agents combined with a taxane appears to be the preferred application of HER2 + MBC.

Importance: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence., Objectives: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality., Design, Setting, and Participants: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019., Exposures: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis., Main Outcomes and Measures: The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method., Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55)., Conclusions and Relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.

Background: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses., Methods: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted., Results: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm., Conclusions: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Purpose: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely., Methods: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival., Results: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006)., Conclusions: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Purpose: In adjuvant settings of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, anthracycline-based chemotherapy followed by taxane and trastuzumab is a standard regimen. Recent studies have reported the use of anthracycline-free adjuvant chemotherapy in selected HER2-positive breast cancer patients. We conducted a single-center retrospective study to identify the characteristics of HER2-positive breast cancer patients for whom anthracyclines can be safely omitted., Methods: A total of 238 women were diagnosed with HER2-positive breast cancer and treated with neoadjuvant and/or adjuvant chemotherapy between January 1, 2008 and December 31, 2015 at Keio University Hospital. They were divided in two cohorts: an "anthracycline" cohort of 112 anthracycline-treated women and a "no anthracycline" cohort of 126 anthracycline-untreated women. Survival outcomes were estimated by Kaplan-Meier method., Results: The 3-year disease-free survival rates in the no-anthracycline and anthracycline cohorts were 91.3% and 93.1%, respectively (P = 0.692). After using a statistical method with inverse probability of treatment weighting to minimize the selection bias, no significant differences were observed between the two cohorts (adjusted hazard ratio for disease-free survival: 1.042; P = 0.909). Stratified by tumor size, no significant differences were observed between the two cohorts in the cT1N0 and cT2N0 subsets (P = 0.516 and P = 0.579, respectively). The recurrence rate was low among patients who achieved pathological complete response after receiving neoadjuvant chemotherapy with or without anthracyclines., Conclusion: Our study suggests that anthracyclines can be safely omitted in selected patients with HER2-positive breast cancer, who have cT1N0 or cT2N0 and achieved pathological complete response after receiving neoadjuvant chemotherapy.

Purpose: To evaluate and compare the efficacy and safety of the taxane plus anthracycline (TA) regimen vs. the taxane plus anthracycline plus cyclophosphamide (TAC) regimen as adjuvant chemotherapy in Chinese patients with node-positive breast cancer (BCa)., Methods: Patients with BCa (n = 640) were recruited between January 2010 and June 2012. All patients were randomized to receive six cycles of adjuvant therapy with the TA or TAC regimen. The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS), quality of life (QoL), and chemotherapy-related toxicity. Finally, 630 patients were evaluable, with a median follow-up of 70 months., Results: There were no differences in the 70-month median DFS and OS between the two groups (DFS: TA 79.7% vs. TAC 75.6%, P = 0.371; OS: TA vs. TAC, 85.1% vs. 87.6%, P = 0.271). The TA group had lower frequencies grade III/IV vomiting (TA vs. TAC, 11.7% vs. 18.1%, P = 0.025) and nausea (13.0% vs. 19.4%, P = 0.031). The health-related QoL score was higher in the TA group (74.1 ± 5.3 vs. 67.9 ± 4.4, P = 0.001 vs. TAC)., Conclusions: In the adjuvant setting, compared with the TAC regimen, the TA regimen exhibits no significant difference with respect to DFS and OS in Chinese patients with node-positive BCa. On the other hand, TA is associated with less severe adverse events, lower economic burden, and better QoL.