Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features. This study aimed to determine the molecular effects of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS. METHODS: Patients with HER2 positive DCIS received 1,500 mg daily of lapatinib for four consecutive weeks prior to surgical resection. Magnetic resonance imaging (MRI) was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki67 and p27) and apoptosis (TUNEL) were determined in pre and post-lapatinib treatment samples. RESULTS: A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki67. CONCLUSIONS: Four weeks of neoadjuvant lapatinib in patients with HER2-positive DCIS resulted in inhibition of HER2 and RAS/MAPK signaling pathway. TRIAL REGISTRATION: 2008-004492-21 (Registered June 25th 2008).

An analysis of the association between breast density and body mass index with breast cancer molecular subtypes in early breast cancer: data from a Spanish population.

PURPOSE: Breast cancer is an important health problem, like obesity and dyslipidemia, with a strong association between body mass index (BMI) and breast cancer incidence and mortality. The risk of breast cancer is also high in women with high mammographic breast density (MBD). The purpose of this study was to analyze the association between BMI and MBD according to breast cancer molecular subtypes. METHODS: This transversal, descriptive, multicenter study was conducted at three Spanish breast cancer units from November 2019 to October 2020 in women with a recent diagnosis of early breast cancer. Data were collected at the time of diagnosis. RESULTS: The study included 162 women with a recent diagnosis of early breast cancer. The median age was 52 years and 49.1% were postmenopausal; 52% had normal weight, 32% overweight, and 16% obesity. There was no association between BMI and molecular subtype but, according to menopausal status, BMI was significantly higher in postmenopausal patients with luminal A (p = 0.011) and HER2-positive (p = 0.027) subtypes. There was no association between MBD and molecular subtype, but there were significant differences between BMI and MBD (p < 0.001), with lower BMI in patients with higher MBD. Patients with higher BMI had lower HDL-cholesterol (p < 0.001) and higher insulin (p < 0.001) levels, but there were no significant differences in total cholesterol or vitamin D. CONCLUSIONS: This study showed higher BMI in luminal A and HER2-positive postmenopausal patients, and higher BMI in patients with low MBD regardless of menopausal status.

A Phase II study of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of capecitabine in combination with vinorelbine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: In this prospective, multicenter, open-label phase II trial, patients received capecitabine (2000 mg/m2 daily, taken in 2 oral doses) on days 1-14 and vinorelbine (25 mg/m2 intravenous infusion) on days 1 and 8. Cycles were repeated every 3 weeks up to a maximum of 6 cycles, unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. RESULTS: Thirty-one patients were included and received 152 cycles of chemotherapy, with a median of 3 cycles per patient. All patients were evaluated for efficacy and toxicity in an intent-to-treat analysis. The overall response rate was 49% (95% CI, 30%-67%), including 4 complete (13%) and 11 partial (36%) responses. With a median follow-up time of 9 months, the median time to disease progression was 7.6 months (95% CI, 5.7-9.8 months), and the median survival time was 27.2 months. The most frequent severe hematologic toxicities were neutropenia (48% of patients) and leukopenia (10% of patients). Vomiting (16% of patients) was the most common nonhematologic toxicity, while asthenia, bone pain, dyspnea, plantar-palmar erythrodysesthesia, nausea, and transaminase elevation were observed in 6%-10% of patients. There was 1 death from septic shock. CONCLUSION: Capecitabine in combination with vinorelbine is an effective and safe schedule for patients with MBC pretreated with anthracycline- and taxane-containing regimens.

Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial.

PURPOSE: There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial. PATIENTS AND METHODS: Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS. RESULTS: Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. CONCLUSION: This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials.

Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of efficacy or tolerance. The suitability of the control arm, the prospective definition of patient's subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel.

The use of taxanes in the neoadjuvant treatment of breast cancer: a review of randomized phase II/III trials.

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.

Optofluidic device for the quantification of circulating tumor cells in breast cancer.

Metastatic cancer patients require a continuous monitoring during the sequential treatment cycles to carefully evaluate their disease evolution. Repetition of biopsies is very invasive and not always feasible. Herein, we design and demonstrate a 3D-flow focusing microfluidic device, where all optics are integrated into the chip, for the fluorescence quantification of CTCs in real samples. To test the chip performance, two cell membrane targets, the epithelial cell adhesion molecule, EpCAM, and the receptor tyrosine-protein kinase, HER2, are selected. The efficiency of the platform is demonstrated on cell lines and in a variety of healthy donors and metastatic-breast cancer patients.

Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer.

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling > or =30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.

Weekly docetaxel as neoadjuvant chemotherapy for stage II and III breast cancer: efficacy and correlation with biological markers in a phase II, multicenter study.

PURPOSE: This is one of the first reports of weekly docetaxel (Taxotere) in the neoadjuvant treatment of stage II and III breast cancer. We evaluated docetaxel's efficacy and safety and analyzed correlations between response and the expression of c-erbB2, ER status, and Ki-67 labeling index. EXPERIMENTAL DESIGN: Patients with previously untreated, stage II and III breast cancer were entered into the study. Docetaxel (40 mg/m(2)) was given i.v. once weekly for the first 6 weeks of an 8-week cycle for 2 cycles. RESULTS: A total of 56 patients were evaluated by intention-to-treat analysis for efficacy and safety. The overall clinical response rate was 68% (complete and partial response, 29 and 39%, respectively). Nine patients (16%) achieved a pathological complete response. There was no correlation between response to docetaxel and the expression of molecular markers, however, the majority of the pathological complete responses were observed in patients with c-erbB2-negative tumors. Nonhematological toxicity was more common than hematological toxicity, with alopecia and asthenia the most frequently reported adverse events (89 and 77% of patients, respectively). Severe hematological toxicity was rare. CONCLUSIONS: Weekly docetaxel appears to be very effective in the neoadjuvant setting. A high pathological response rate was achieved with tolerable toxicity.

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy in stage II and III breast cancer patients: preliminary results of a phase II and pharmacogenomic study.

The purpose of this study is to evaluate the efficacy and safety of a biweekly neoadjuvant docetaxel/gemcitabine regimen in patients with histologically confirmed stage II and III breast cancer. In addition, a cDNA microarray study attempted to correlate pretreatment gene-expression profile with clinical and pathologic responses. Docetaxel 65 mg/m(2) was given in a 60-minute intravenous infusion followed by gemcitabine 2,500 mg/m(2) in a 30-minute intravenous infusion every 2 weeks for six cycles; prophylaxis with growth factors was allowed. Four cycles of standard AC (doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)every 21 days) was routinely delivered to all patients postsurgery. Thirty patients are accrued on-study so far. The overall response rate for 24 evaluable patients was 79% (95% confidence interval, 9.7 to 53.5) with six complete responses and 13 partial responses. One patient (4%) out of 23 achieved a pathologic complete response in the breast at the time of definitive surgery. Breast conservation procedure was possible in 14 patients (61%). A total of 161 cycles has been delivered. Grade 1/2 alopecia and a mild grade 1/2 LDH increase were the most frequently reported adverse events (78% and 55% of cycles, respectively). Grade 3/4 neutropenia was reported in 18 cycles (11%). These preliminary results show that biweekly docetaxel and gemcitabine is an optimal regimen as neoadjuvant treatment of stage II and III breast cancer. In spite of the large tumor size, breast conservation was possible in 61% of the patients. In general, toxicity was very manageable.

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer.

Third-generation aromatase inhibitors (AIs) have proven to be superior to tamoxifen in terms of time to disease progression in patients with hormone receptor (HR) positive (HR+) status and, nowadays, are used in the adjuvant and neoadjuvant settings, and first-line therapy for advanced breast cancer. Letrozole is a third generation AI, as are anastrozole and exemestane. In the past, clinical studies had demonstrated that letrozole was effective as a second-line treatment of metastatic breast cancer. In this paper, pharmacokinetic and pharmacodynamic properties of letrozole are reviewed along with its activity in preclinical and clinical settings. Additionally, the results of important clinical trials such as Breast International Group (BIG) 1-98, which tested the optimal initial adjuvant endocrine treatment and the sequential therapy with letrozole and tamoxifen, MA-17 that evaluates the benefits of extended adjuvant therapy, and other important studies in advanced and neoadjuvant disease, are reviewed. Safety comparisons of treatments are also addressed. Interestingly, about 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers are HR+. However, HER2 positivity is a marker of antiestrogen treatment resistance. Because of this, a dual treatment is a logical approach when both receptors are overexpressed. The combination of lapatinib and letrozole leads to a significant improvement in the overall disease outcome. Also, the combination of everolimus plus letrozole has been tested in this setting. In fact, the coadministration of both agents seems to increase the efficacy of letrozole in newly-diagnosed HR+ patients. Once resistance to sequential trastuzumab and AI as monotherapy has been found, trastuzumab and letrozole combined in HR+ and HER2+ patients with advanced breast cancer can overcome resistance to both drugs administered as single agents, according to recently reported results.

Current perspectives of treatment of ductal carcinoma in situ.

DCIS is a genetically diverse group of diseases with different prognosis. The similarities between DCIS and ductal infiltrating carcinoma (DIC) suggest that the key step in tumorigenesis is the transformation from high grade ductal hyperplasia to DCIS. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. The key questions for DCIS management include: which patients are more likely to present an invasive failure; in which an excision is sufficient and who can be spared from radiation therapy. The role of post operative radiation therapy to reduce by 50-60% ipsilateral invasive and non-invasive local failure has been established in four randomized clinical trials. The question whether radiation therapy can be avoided in some patients remains controversial. Treatment with tamoxifen should be recommended to patients with estrogen receptor positive tumors who have been treated with conservative surgery. However, data from randomized trials suggest that addition of tamoxifen to locoregional treatment decreases the recurrence rate of invasive cancer as well as contralateral tumors. Sentinel lymph node biopsy is recommended for patients with clinically palpable, large DCIS in which the risk of microinvasion is high as well as in extensive DCIS requiring mastectomy. Mammography continues to be the best method to detect DCIS. Newer digital mammography improves the detection of microcalcifications. Current ultrasound can detect associated invasive cancer. MRI is also useful in DCIS. Combined with mammography, MRI increases the diagnoses of DCIS. Current trend includes the use of radiology guided-vacuum assisted-large bore needles that allow obtaining larger amounts of tissue, improving diagnostic yield.

Evaluation of international treatment guidelines and prognostic tests for the treatment of early breast cancer.

The clinical decision to treat early-stage breast cancer with adjuvant chemotherapy is sometimes a difficult one because 70-80% of patients who receive chemotherapy would probably have survived without it. To help clinicians in this decision-making process, different tools or 'decision aids' have been developed for the treatment of early breast cancer over the years. Some of these tools include clinical treatment guidelines and computer-based programs as well as different prognostic and/or predictive tests such as those based on gene expression profiles or the presence minimum invasive disease. All of these tools try to individualize as much as possible the estimation of the risk of breast cancer relapse and death and to facilitate the clinical decision about giving additional treatment, and ultimately the most appropriate treatment to be given. Thus, it is important for clinicians to be aware of not only the existence of these tools or 'decision aids', but also to know how they have been developed, how frequently there are revised and if they have been validated. In order to address all these concerns, we have carried out a critical review of the most important prognostic tests and clinical guidelines for the treatment of early breast cancer. Information regarding their development process as well as frequency of revision, validations that have been performed and main limitations of each tool were gathered and critically analyzed.

Neoadjuvant endocrine therapy for breast cancer: past, present and future.

Combined treatments together with surgery, radiotherapy, chemotherapy, and endocrine therapy have contributed substantially to the improved survival rate in breast cancer. For more than 2 decades, tamoxifen has been the standard endocrine agent for hormone receptor-positive tumors. Third-generation aromatase inhibitors have, however, now proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. They have especially improved the surgical management of large or inoperable locally advanced breast tumors. Other advantages of neoadjuvant endocrine therapy are just emerging, but there are still many unanswered questions regarding its optimal use in this setting. A need to define how to select the patients who will benefit most from these therapies, the optimal duration of treatment, the best method to evaluate the treatment response achieved, the existence of predictive factors for response, or the superiority of certain endocrine agents over others has been observed. Other questions regarding which complementary local and systemic treatments should be administered after neoadjuvant endocrine therapy or which efficacy endpoints should be evaluated in clinical trials are also of interest. To answer as many of these questions as possible, we have carried out a critical analysis of the current literature on the use of endocrine therapy in the neoadjuvant setting of breast cancer. In this review, we outline the rationale for its use, and consider data published to date to further clarify how to optimize its administration.

Advanced breast cancer: chemotherapy phase III trials that change a standard.

At the present time, there is not a standard regimen in upfront metastatic setting for breast cancer. A wide variety of regimens which includes anthracyclines, taxanes, gemcitabine or capecitabine are currently used, however, there is evidence to support the use of many of these drugs in early breast cancer and consequently limiting their use in first line treatment. The aim of this review is to evaluate every randomized phase III trials conducted in first line metastatic breast cancer. For this reason, all randomized studies that evaluated the role of chemotherapy in advanced breast cancer were analyzed and classified according to their protocol design. So far, sixteen major randomized clinical trials have evaluated the role of chemotherapy as front line in metastatic breast cancer. Some of them have analyzed a different anthracyclines-based regimen as the control arm versus new combinations or new drugs. In others, the aim is to evaluate the most effective therapy after progression to an adjuvant anthracyclines-containing regimen. The suitability of the control arm, the prospective definition of patient's subgroups as well as the statistical methodology have been taken into account.