Optimal timing for adjuvant radiation therapy in breast cancer: A comprehensive review and perspectives

Purpose

The optimal sequence of modalities involved in breast cancer treatment with respect to radiotherapy and the maximum acceptable interval between radiotherapy and surgery need to be determined.

Design

This review attempts a critical reading of the literature.

Results

A delay of radiotherapy more than 8-12 weeks after surgery adversely affects local recurrence. Radiotherapy should be administered within 7 months after surgery, when chemotherapy is administered first. Several chemotherapy regimens can be safely administered concurrently with radiotherapy. The concurrent use of tamoxifen with chemotherapy should be avoided, but not with radiotherapy. Data is insufficient with regard to concurrent use of aromatase inhibitors with radiotherapy. The use of trastuzumab concomitantly with radiotherapy may enhance toxicities but may also improve its efficacy.

Conclusions

Although the issue of radiotherapy delay and that of sequence with chemotherapy or tamoxifen are clarified, the sequence of radiotherapy with aromatase inhibitors and trastuzumab needs to be defined. Individual radiosensitivity may influence toxicity. New biologic markers have to be determined in the future for tailoring radiotherapy in breast cancer.     

Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment

Background

In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse.

Method

In this study, CETC were monitored using the Maintrac^® method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib.

Results

In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease.

Conclusions

In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

     

The predictive role of phosphatase and tensin homolog (PTEN) loss,phosphoinositol-3 (PI3) kinase (PIK3CA) mutation,and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Abstract

Objective:

Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be related to trastuzumab resistance in in vitro studies; however, this issue in clinical studies is controversial. Therefore, we conducted a meta-analysis to assess the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in HER2-positive breast cancer patients.     

V‐ATPase inhibition overcomes trastuzumab resistance in breast cancer

The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H+‐ATPase (V‐ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V‐ATPase opens a new therapeutic strategy against trastuzumab‐resistant tumor cells in vitro and in vivo. V‐ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro‐survival signaling of the trastuzumab‐resistant cell line JIMT‐1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT‐1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2‐recycling which leads to reduced tumor growth. These results suggest that V‐ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab‐resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2‐signaling in vitro as well as in vivo. V‐ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab‐resistant tumors.     

Effectiveness of Trastuzumab in First‐Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

Background.

The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting.

Materials and Methods.

By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006–2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis.

Results.

Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50–1.26).

Conclusion.

Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials.     

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review

Trastuzumab, a key treatment for HER2-positive breast cancer, is available in weight-based IV and fixed-dose (600 mg) SC formulations. While the Phase 3 HannaH trial indicated non-inferiority of the SC formulation, there is some concern that the target plasma concentration may not be reached in overweight/obese patients whereas low-body-weight patients may be at risk of toxicity.This scoping review evaluated whether overweight/obese patients are at risk of below-target exposure with fixed-dose SC trastuzumab, whether low-body-weight patients are at risk of increased toxicity, especially cardiotoxicity, and whether IV and SC trastuzumab are equivalent in terms of treatment-emergent adverse events (TEAEs) (e.g. infections). Thirty-seven publications that met the eligibility criteria were included.Body weight is not an important determinant of exposure to trastuzumab at steady state (i.e. pre-dose cycle 8); however, real-world evidence suggests that the target concentration (20 μg/mL) may not be reached with the first SC dose in overweight/obese patients. There is no evidence that low-body-weight patients are at increased risk of cardiotoxicity with SC trastuzumab, although this may be confounded by the higher rate of cardiovascular comorbidities in overweight patients. In Phase 3 trials, SC trastuzumab was associated with higher rates of ISRs, ADAs and SAEs, the latter often requiring hospitalization and occurring during adjuvant treatment when patients are not burdened by chemotherapy.The route of administration of trastuzumab (IV vs SC) in different treatment settings should be discussed with the patient, taking into account the risks and benefits associated with each route.     

Cost-effectiveness of trastuzumab biosimilar combination therapy and drug wastage as first-line treatment for HER2-positive metastatic breast cancer

BackgroundThe rising cost of cancer drug therapy threatens the long-term sustainability of Taiwan National Health Insurance. Cost savings can be achieved through various strategies, e.g., using smaller vial sizes, sharing vials, weight-based dosing, or switching to biosimilars. Here we aimed to examine the cost-effectiveness of a trastuzumab biosimilar combined with docetaxel (TDbiol) for treatment-naïve HER2⁺ metastatic breast cancer (MBC), and the financial impact of drug wastage.MethodsA Markov model with three health states was developed to assess the cost-effectiveness of trastuzumab biosimilars plus docetaxel over a 40-month time horizon in patients with HER2⁺ MBC. Based on the literature and our expert opinion, we assumed similar efficacy between the trastuzumab biosimilar and its reference product. The primary clinical input for the biosimilar was the same as for the reference product in the Catastrophic Patient Database (HV). Health state utilities were derived from the literature, and direct medical costs were obtained from the National Health Insurance Administration (NHIA).ResultsIn the base-case scenario, the incremental cost-effectiveness ratio (ICER) was NTD 811,050 per QALY gained. One-way sensitivity analyses showed that the model was sensitive to utilities and transition probabilities, but not particularly sensitive to the wastage assumption. In scenario analyses, the ICER was higher when applying the price for trastuzumab reference biologic (branded), than for trastuzumab biosimilar.ConclusionThe trastuzumab biosimilar combination regimen is cost-effective and offers significant drug cost savings in Taiwan.     

Efficacy of CT-P6 (trastuzumab biosimilar) versus reference trastuzumab in combination with pertuzumab in HER2-positive early-stage breast cancer: Preclinical and real-life clinical data

After the expiration of trastuzumab data exclusivity, biosimilar drugs were approved by regulatory agencies; among them, CT-P6 which was approved for the treatment of HER2-positive early- and advanced-breast cancer (BC) in 2018. Yet, reference trastuzumab (RTZ) is often combined with pertuzumab in early BC (EBC) patients treated with chemotherapy as it significantly improves the pathological complete response rate. Unfortunately, scarce preclinical and clinical data exists about the combination of CT-P6, pertuzumab and chemotherapy. Therefore, our aim was to study in vitro and in a retrospective cohort of EBC patients, whether CT-P6 was equivalent to RTZ when combined with pertuzumab with or without taxanes. In BT-474 and SKBR3 HER2+ cells we found that CT-P6 alone or in combination with pertuzumab had the same negative effect on cell proliferation, colony formation and HER2 downregulation as well as downstream activation, as RTZ. Adding paclitaxel to these treatments increased their effectivity to a similar extent. In HER2 1+ neuregulin-secreting MB-MDA-175 cells, combinations of CT-P6 or RTZ with pertuzumab were also effective, and mainly dependent on HER3:HER2 heterodimerization. In a retrospective cohort of 44 EBC HER2+ patients treated with neoadjuvant RTZ or CT-P6 in combination with pertuzumab and chemotherapy, we found no differences in efficacy or in adverse events. Moreover, the costs of CT-P6-based treatments were reduced by 1474.07 €/patient. All together we provide pre-clinical and clinical evidence of the equivalence of CT-P6 in combination with pertuzumab and chemotherapy and suggest studying these combinations also in HER2 low/negative BC patients.