To date, only few marine natural compounds have been proved to be active in breast cancer (BC). The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents ...(eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders—trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs). Notably, eribulin is the only approved cytotoxic drug for the treatment of advanced BC (ABC), while cytarabine has a limited indication in case of leptomeningeal diffusion of the disease. Also plocabulin showed limited activity in ABC but further research is needed to define its ultimate potential role. The available clinical data for both trabectedin and lurbinectedin are of particular interest in the treatment of BRCA-mutated tumours and HR deficient disease, probably due to a possible immune-mediated mechanism of action. One of the most innovative therapeutic options for the treatment of BC, particularly in TNBC and HER2-positive BC, are ADCs. Some of the ADCs were developed using a specific marine-derived cytotoxic molecule as payload called auristatin. Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.
Purpose: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit
in women with HER2-positive metastatic breast cancer, mediates its ...antitumor activity.
Experimental Design: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed.
Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was
surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients
were collected for biological studies.
Result: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation
Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function
were observed during this short-term treatment and after surgery. The biological data showed that, independent of response,
( a ) all patients showed high levels of circulating trastuzumab; ( b ) saturating level of trastuzumab was present in all of the tumors; ( c ) no down-modulation of HER2 was observed in any tumors; ( d ) no changes in vessel diameter was observed in any tumors; ( e ) no changes in proliferation was observed in any tumors; and ( f ) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission
were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity.
Conclusions: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor
of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.
Clinical trials confirmed the beneficial effects of adding pertuzumab (P) to the combination of trastuzumab-chemotherapy (TC) in the (neo)adjuvant setting of high-risk HER2-positive early breast ...cancer (HER2+BC). We evaluated the clinical, economic and societal impact of adding pertuzumab to neoadjuvant TC combination (TPC) in Italy.
A cost-consequence analysis comparing TPC vs. TC was performed developing a cohort-based multi-state Markov model to estimate the clinical, societal and economic impact of the neoadjuvant therapy of TPC versus TC in HER2+BC at high-risk of recurrence. The model works on a cycle length of 1 month and 5-years-time horizon. Literature review-based data were used to populate the model. The following clinical and economic outcomes were estimated: cumulative incidence of loco-regional/distant recurrences, life of years and QALY and both direct and indirect costs (€). Finally, sensitivity analyses were performed.
TPC was associated with a 75,630 € saved of direct costs. Specifically, it was associated with an initial increase of treatment costs (+4.8%) followed by reduction of recurrence management cost (−20.4%). TPC was also associated with an indirect cost reduction of 1.40%, as well as decreased incidence of distant recurrence (−20.14%), days of work lost (−1.53%) and days lived with disability (−0.50%). Furthermore, TPC reported 10,47 QALY gained (+2.77%) compared to TC. The probability to achieve the pathological complete response (pCR) was the parameter that mostly affected the results in the sensitivity analysis.
Our findings suggested that TPC combination could be a cost-saving option in patients with HER2+BC at high-risk of recurrence.
•TPC in the (neo)adjuvant setting is an effective treatment in high-risk HER2-positive early breast cancer.•TPC in the (neo)adjuvant setting is reimbursed in many European countries but not in Italy.•In our analysis, TPC was associated with a 124,956 € saved per 100 treated patients over 5-year time horizon compared to TC.•TPC showed a reduction of distant recurrence (−20.14%), days of work lost (−1.53%) and days lived with disability (−0.50%).•TPC showed a cost-saving profile in patients with HER2-positive early BC at high-risk of recurrence compared to TC.
Breast cancer is the most common malignancy among women worldwide, and HER2-positive breast cancer accounts for approximately 15% of all breast cancer diagnoses. The advent of HER2-targeting ...therapies has dramatically improved the survival of these patients, significantly reducing their risk of recurrence and death. However, as a significant proportion of patients ultimately develop resistance to these therapies, it is extremely important to identify new treatments to further improve their clinical outcomes. Immunotherapy has revolutionized the treatment and history of several cancer types, and it has already been approved as a standard of care for patients with triple-negative breast cancer. Based on a strong preclinical rationale, immunotherapy in HER2-positive breast cancer represents an intriguing field that is currently under clinical investigation. There is a close interplay between HER2-targeting therapies (both approved and under investigation) and the immune system, and several new immunotherapeutic strategies, including immune checkpoint inhibitors, CAR-T cells and therapeutic vaccines, are being studied in this disease. In this narrative review, we discuss the clinical evidence and the future perspectives of immunotherapy for patients with HER2-positive breast cancer.
Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), ...the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.
Background During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To ...longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D. Methods aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1). Results As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI 210-354 vs 56-209, log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI 255-444 vs 45-232, log-rank test p=0.009). Conclusions HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors. Trial registration NCT05735392 retrospectively registered on January 31, 2023 Keywords: HER2-positive breast cancer, Trastuzumab emtansine (T-DM1), Liquid biopsy, Circulating cell-free DNA (cfDNA), Circulating soluble HER2 (sHER2)
The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation ...between these patterns and oncological results was described. Our aims were to define the predictive factors for different patterns of residual disease and compare the outcomes between the scattered versus the circumscribed pattern.
We reviewed 219 postoperative surgical specimens. Patients were divided into two groups: scattered versus circumscribed. Disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were analyzed.
The scattered and circumscribed patterns were assessed in 111 (50.7%) and 108 (49.3%) patients. Two independent predictive factors for the circumscribed pattern were identified: discontinuation of NAC cycles (
= 0.011), and tumor size post-NAC >18 mm (
= 0.022). No difference was observed in terms of DFS and DDFS. Patients with the scattered pattern exhibited a statistically significant better OS. Discontinuation of NAC cycles, tumor size >18 mm, triple-negative BC, and ypN+ were associated with increased recurrence and poorer survival.
Discontinuation of NAC cycles and tumor size are independent factors associated with patterns of residual disease. The scattered pattern presents better survival. Understanding the relationship between NAC, the residual pattern, and differences in survival outcomes offers the potential to optimize the therapeutic approaches.
Background: Breast units (BUs) provide breast cancer (BC) care, including prevention, treatment, and genetic assessment. Genetic research has highlighted BRCA1/2 mutations as key hereditary BC risk ...factors. BRCA testing is crucial for personalized treatment and prevention strategies. However, the integration of BRCA testing in Italian BUs faces multiple challenges. This study, by Senonetwork Italia, aimed to evaluate genetic testing practices and identify obstacles within Italian BUs. Methods: Senonetwork Italia conducted a 16-question web-based survey involving 153 BUs. The survey assessed aspects of BRCA testing, including timing, urgency, counseling, patient selection, and multi-gene panels. Results: Of the 153 BUs, 109 (71.2%) responded. Testing before surgery was performed by 70.6% of centers, with urgent cases acknowledged by 87.2%. Most centers (56.0%) arranged urgent pre-test counseling within a week. BRCA mutation status influenced treatment decisions in 99.1% of cases. Multi-gene panels were used by 33.0% of centers for all genetic counseling cases, while 56.0% followed standard referral criteria. The main challenges included cost, reimbursement, and reporting timelines. Conclusions: This survey highlights significant variations in BRCA testing practices across Italian BUs and identifies key logistical and financial challenges. There is a need for standardized practices of genetic testing to ensure personalized and effective BC management in Italy.
Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone ...receptor-positive/HER2-negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormone-positive/HER2-negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2-negative early breast cancers.
The potential role of circulating microRNAs (miRNAs) as biomarkers in breast cancer (BC) management has been widely reported. However, the numerous discrepancies between studies in this regard ...hinders the implementation of circulating miRNAs in routine clinical practice. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of predicting NAC response may lead to prognostic improvements by individualizing post-neoadjuvant therapy. In this context, the present meta-analysis aims to clarify circulating miRNAs' predictive role with respect to NAC response among BC patients. We conducted a comprehensive literature search on five medical databases until 16 February 2023. We pooled the effect sizes of each study by applying a random-effects model. Cochran's Q test (
-level of significance set at 0.05) scores and I
values were assessed to determine between-study heterogeneity. The PROBAST (Prediction Model Risk of Bias Assessment Tool) tool was used to evaluate the selected studies' risk of bias. Overall, our findings support the hypothesis that circulating miRNAs, specifically miR-21-5p and miR-155-5p, may act as predictive biomarkers in the neoadjuvant setting among BC patients. However, due to the limited number of studies included in this meta-analysis and the high degrees of clinical and statistical heterogeneity, further research is required to confirm the predictive power of circulating miR-21-5p and miR-155-5p.
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