Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm ...studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting.
Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life.
Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), corrected and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms.
In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.
An earlier report documented significant improvement in progression-free survival among patients with metastatic breast cancer treated with fulvestrant and a cyclin-dependent kinase inhibitor, ...ribociclib. With longer follow-up, it is clear that fulvestrant and ribociclib also prolong overall survival.
Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC ...(aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory Value (PIV), defined as the product of peripheral blood neutrophil, platelet, and monocyte counts divided by lymphocyte counts, on the prognosis of HER2+ aBC patients treated with first line trastuzumab-pertuzumab-based biochemotherapy. We also evaluated the association between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte to lymphocyte ratio (MLR) and clinical outcomes. Cox regression models were used to estimate the impact of these variables, as well as of other clinically relevant covariates, on patient survival. We included 57 HER2+ aBC patients treated with taxane-trastuzumab-pertuzumab in our Institution. High baseline MLR, PLR, and PIV were similarly predictive of worse PFS at univariate analysis, but only high PIV was associated with a trend toward worse PFS at multivariable analysis. Regarding OS, both high PIV and MLR were associated with significantly worse patient survival at univariate analysis, but only the PIV was statistically significantly associated with worse overall survival at multivariable analysis (HR 7.96; 95% CI: 2.18-29.09). Our study reveals the PIV as a new and potent predictor of OS in HER2+ aBC patients treated with first line trastuzumab-pertuzumab-containing biochemotherapy. Prospective studies are needed to validate this new prognostic parameter in HER2+ aBC.
The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2- mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 ...trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2- mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2- mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2- BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status.
Based on the available efficacy and safety data, the "new" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the "old" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2- mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.
Few studies have investigated the needs of patients with metastatic breast cancer (MBC), and none have been conducted in Italy. Three categories of needs have been identified from the literature: ...information, support, and practical resources. The present study aims to achieve an in-depth understanding of the patients’ needs related to the MBC care pathway. In-depth interviews were conducted and analyzed by thematic analysis. The participants were 9 women with MBC (age range 36–74) who were enrolled at the Fondazione IRCCS Istituto Nazionalde dei tumori, in Milan. The analysis enabled us to identify four themes (which reflect the needs of the participants), each divided into numerous sub-themes: (1) the need for clinical recognition, (2) the need for more attention from healthcare professionals, (3) the need for more and better services to be available at the hospital, (4) the need for specific public health policies. Since the metastatic phase of breast cancer seems to elicit additional, specific needs and multi-level management, changes in attitudes and multidisciplinary practices should be tested in order to ascertain how these needs can be met.
Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumour cell ...proliferation.
The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging. Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models.
Overall, 287 patients were enroled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (hazard ratio HR, 2.21; 95% confidence interval 95% CI, 1.45, 3.37; P = 0.0002); similar results were observed for patients with high sTKa levels at C1D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression versus the pattern with low sTKa levels at both time points (HR, 2.89; 95% CI, 1.57, 5.31; P = 0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR, 5.65; CI: 2.84, 11.2; P < 0.0001). Baseline and dynamic sTKa changes provided independent information.
sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2– ABC treated with ribociclib plus letrozole as first-line therapy.
•sTKa is a biomarker of outcome in ribociclib plus letrozole-treated HR+, HER2– ABC.•sTKa levels are strongly prognostic of mPFS at different time points.•sTKa early dynamic changes predict mPFS independently of prognosis by baseline sTKa.•sTKa early dynamic changes may be associated with inherent underlying tumour biology.
Aromatase inhibitors (AIs) as adjuvant therapy after breast cancer (BC) surgery have demonstrated to reduce the risk of disease recurrence, to lower the risk of contralateral BC, and to improve ...survival when compared to tamoxifen in patients with limited-stage hormone receptor-positive (HR+) BC. However, AIs are associated with adverse events that can have a significant impact on patient quality of life (QoL).
This study aimed to identify profiles of psychological symptoms and QoL in HR+ BC patients undergoing AI therapy.
Data were collected with questionnaires administered at three time points: AI initiation (t0); 3 months after AI initiation (t1); and 6 months after AI initiation (t2). The FACT-G, FACT-B, and FACT-ES questionnaires were used to assess QoL; psychological symptoms were assessed using the SCL-90-R.
43 women were enrolled in the study (t0), and 37 completed the t1 evaluation and 29 the t2 evaluation. We found (1) a progressive decrease over time in FACT-G and FACT-ES scores, in particular in the Physical, Emotional, and Endocrine subscales, and an increase in the SOM (somatization) subscale of the SCL-90-R; (2) the presence of 4 clusters related to different psychological symptoms and QoL evolution over time; (3) that patients belonging to the cluster characterized by worsening symptoms and QoL during time differed from the others in the Emotional subscale of the FACT-B and in the GSI (Global Score), OCD (obsessive-compulsive), DEP (depression), ANX (anxiety), and SLP (sleep disorders) dimensions of the SCL-90-R and had significantly higher BMI levels; and (4) that 3 items from the SCL-90-R and 2 items from FACT Emotional Well-Being subscale were predictive of the "worst" cluster.
Although larger studies are needed to confirm these results, our data open up new ways of investigation into the effects of AIs on QoL in HR+ BC patients.
In the MONALEESA-3 Phase III trial of patients with hormone receptor–positive human epidermal growth factor receptor–negative advanced breast cancer, ribociclib plus fulvestrant significantly ...improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL).
Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status GHS from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs.
Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 95% CI, 0.62–1.1). Similar findings were noted for TTD ≥5% (HR = 0.79 95% CI, 0.61–1.0) and TTD ≥15% (HR = 0.81 95% CI, 0.60–1.08). TTD ≥10% in emotional functioning (HR = 0.76 95% CI, 0.57–1.01) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 95% CI, 0.57–1.05) and worst pain item score (HR = 0.81 95% CI, 0.58–1.12) trended in favor of ribociclib vs placebo.
In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL.
•Ribociclib + fulvestrant allowed maintenance of global health status (GHS).•Time to deterioration (TTD) by 10% can convey duration until worsening of QOL.•TTD ≥10% was delayed with ribociclib in GHS and emotional functioning.•Ribociclib also demonstrated trends toward delayed TTD vs placebo in pain outcomes.
Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting ...remains unclear.
We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates.
Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009).
CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.
Single-agent chemotherapy, alone or with immunotherapy, represents the first-line standard-of-care treatment for advanced TNBC patients. This study conducted in 88 TNBC patients supports the use of carboplatin-based doublets as first-line regimens and provides evidence of better survival outcomes with carboplatin-gemcitabine among patients previously treated with taxanes in the (neo)adjuvant setting. Future studies are needed to investigate chemo-immunotherapy combinations containing carboplatin-based doublets.
Extramammary Paget disease (EMPD) is a rare form of cutaneous, intraepithelial adenocarcinoma, which typically presents itself as an erythematous plaque originating from apocrine-gland rich regions, ...such as the vulva, the perianal region, the scrotum, the penis, or the axilla. EMPD patients typically have a good prognosis, with expected 5-year survival of 60%–92%, but it is estimated that about one-third of EMPD patients will develop lymph node or distant metastases. Treatment approaches for EMPD include locoregional therapies such as broad surgical resection, radiotherapy, or topical imiquimod, when the disease is localized, and chemotherapy and biological agents for advanced EMPD. We report the case of a 58-year-old man diagnosed with locally advanced, symptomatic HER2-overexpressing, AR-positive EMPD, who achieved long-term tumor control with a sequence of several trastuzumab-based treatments (more than 30 months with second-line carboplatin plus paclitaxel plus trastuzumab followed by trastuzumab maintenance; 9 months for third-line vinorelbine plus trastuzumab). Even if it is reported that AR expression occurs concomitantly with HER2 overexpression in more than half of the cases of EMPD, to the best of our knowledge, this is the first case report describing androgen receptor blockade therapy in combination with an anti-HER2 agent. Our patient did not benefit from androgen receptor blockade in combination with trastuzumab, thus suggesting that AR expression may simply reflect an intrinsic characteristic of the EMPD cell of origin, rather than tumor dependence upon AR signaling. Given the reported sensibility to anti-HER2 therapy, also new antibody drug conjugates targeting HER2 are worth exploring in the management of advanced EMPD.
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