Purpose
To assess the role of radiomics parameters in predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer.
Methods
...Seventy-nine patients who had undergone pretreatment staging
18
F-FDG PET/CT and treatment with NAC between January 2010 and January 2018 were included in the study. Primary lesions on PET images were delineated, and extraction of first-, second-, and higher-order imaging features was performed using LIFEx software. The relationship between these parameters and pCR to NAC was analyzed by multiple logistic regression models.
Results
Nineteen patients (24%) had pCR to NAC. Different models were generated on complete information and imputed datasets, using univariable and multivariable logistic regression and least absolute shrinkage and selection operator (lasso) regression. All models could predict pCR to NAC, with area under the curve values ranging from 0.70 to 0.73. All models agreed that tumor molecular subtype is the primary predictor of the primary endpoint.
Conclusions
Our models predicted that patients with subtype 2 and subtype 3 (HER2+ and triple negative, respectively) are more likely to have a pCR to NAC than those with subtype 1 (luminal). The association between PET imaging features and pCR suggested that PET imaging features could be considered as potential predictors of pCR in locally advanced breast cancer patients.
Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ...ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated.
In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%.
TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio HR, 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001).
TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.
•A strong rationale supports activity of platinum salts in germline BRCA associated tumors.•BRCAassociated tumors achieve impressive pCR rates irrespective of the addition of carboplatin.•In ...metastatic BRCA associated tumors carboplatin showed a clear benefit as compared to taxanes.•Other biomarkers of homologous recombinant deficiency are currently under investigation.•The right schedule of platinum salts and PARP inhibitors needs further investigations.
Germline pathogenic mutations in breast cancer (BC) susceptibility genes (gBRCA1/2) are the most frequent inherited alterations in BC and are involved in the homologous recombination pathway, the principal mechanism of DNA double strand break repair. Platinum salts which act as DNA cross-linking agents are therefore more likely to be active in BRCA-deficient tumors.
Women with gBRCA-associated tumors, particularly with triple negative BC, receiving neoadjuvant platinum containing regimens achieved higher pCR rates as compared to wild-type BC. However in two large randomized trials the addition of carboplatin significantly increased pCR rate only in wild-type tumors.
On the contrary, the randomized TNT trial showed a significant benefit for carboplatin vs docetaxel in terms of response rate and PFS specifically in patients with advanced gBRCA -associated tumors.
Biomarkers of sensitivity to DNA damaging agents beyond gBRCA mutations predicting activity of platinum salts have been proposed and should be validated prospectively.
Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in ...preclinical and clinical studies.
Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks).
In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04).
Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.
Introduction
The interaction between breast cancer and migraine is complex and not fully elucidated. Large epidemiological studies point towards a beneficial effect of migraines on breast cancer ...(BC). We aimed to investigate the BC–migraine relationship, with strict data checks and clinical evaluations of both BC and common headache forms.
Methods
Consecutive BC patients were evaluated with the International Classification of Headache Disorders. Clinical data on the BC subtypes and treatments were collected. Parametric and nonparametric statistics were used according to data distributions.
Results
Fifty patients were recruited. The mean age was 53.5 ± 12.5 years; 42% were postmenopausal, 52% were premenopausal, and 6% were peri-menopausal. Eleven patients were diagnosed as luminal A, nine as luminal B, 24 as HER2-positive (HER2 +), six as triple-negative BC. Thirty-eight (76%) patients had hormone receptor-positive disease. Ninety-two percent received chemotherapy, 66% received endocrine therapy, and 52% received radiotherapy. Nine out of 50 reported a worsening of headache after systemic treatment. Migraine was diagnosed in 29 patients (18 with menstrual migraine), tension-type headache (TTH) in nine, and no headache in 12. Patients with migraine were younger (48.4 ± 10.7 vs. 60.5 ± 12;
p
< 0.01). Patients with migraine and TTH had a higher chance of having a HER2 + BC (
p
< 0.05). Active migraine was associated with a higher expression of estrogen receptors (
p
= 0.04).
Conclusions
Patients with active migraine had higher estrogen receptor expression, while migraine and TTH patients mainly had HER2 + BC. This association was not known earlier and could be helpful to understand deeper the relationship between BC and headache.
We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer ...treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (
,
,
,
,
,
,
,
) showed a statistically significant negative association with PFS. When we considered PFS < 6 months,
,
,
,
,
, and
were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27
and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.
Abstract
We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit ...from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples
ESR1
and
PI3KCA
mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32–92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while
PI3KCA
mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs,
miR-549a
,
miR-644a, miR-16-5p
were negatively while
let-7c-5p
was positively associated with 18-month PFS. In addition
, miR-520d-3p
and
miR-548g-3p
values were significantly lower while
miR-603, miR-181a-5p
and
miR-199a-miR-199b-3p
values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by
miR-603, miR-181a-5p
and
miR-199a-miR-199b-3p.
Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.
Purpose
The most appropriate therapy for HR + /HER2-positive (HER2 +) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome ...the cross-talk between them.
Methods
The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR + /HER2 + ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions.
Results
Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous treatments was 3 (range, 0–10) and F and T were administered as ≥ 3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥ 24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No difference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤ 3 or < 3).
Conclusion
The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression.
De novo metastatic breast cancer (dnMBC) accounts for ~6-10% of all breast cancers and for ~30% of MBC with increasing incidence over time. Hormone receptor-positive/human epidermal growth factor ...receptor 2-negative (HR
/HER2
) tumours are the most frequent subtype with a similar incidence to that observed amongst recurrent MBC (rMBC). Higher frequency of
and
mutations and a lower frequency of
mutations and of genes involved in DNA damage, as compared with rMBC, have been reported in HR
/HER2
dnMBC; however, these are not correlating with prognosis, whilst tumour mutational burden is inversely correlated with outcome. Bone represents the most frequent metastatic site, being the single site in up to 60% of patients with dnMBC. HR
/HER2
dnMBC has been generally reported to have better outcomes than rMBC, with a median overall survival ranging from 26 months to nearly 5 years in patients with favourable features such as age <40 years and bone-only disease, but not when compared with patients with late recurring disease (≥2-5 years). Analyses of the de novo cohorts within randomized clinical trials and large real-world series report a better outcome after treatment with CDK4/6 inhibitors and endocrine agents as compared to rMBC. Despite the limitations of retrospective studies and controversial results of the randomized trials, locoregional treatment of the primary tumour after response to systemic therapy appears to confer a survival benefit, particularly in patients with favourable prognostic factors. Altogether genomic, biological and clinical findings highlight HR
/HER2
dnMBC as a peculiar entity as compared with rMBC and deserve a dedicated treatment algorithm. This article is part of the
Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.
Background:
The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal ...growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials.
Patients and methods:
This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B).
Results:
In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively.
Conclusions:
Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines.
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