Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

Trastuzumab deruxtecan (T-DXd) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Results on T-DXd treatment in HER2-low mBC have so far been limited to clinical trials. DESTINY-Breast Respond HER2-low Europe (NCT05945732) is a multi-center, multi-country, observational, prospective, non-interventional study planning to enroll 1350 patients from 216 sites receiving T-DXd or conventional chemotherapy as their routine clinical care for advanced stage breast cancer in 12 European countries. This non-interventional study will provide real-world insight into T-DXd treatment for HER2-low mBC with data on effectiveness, safety and tolerability, patient-reported outcomes, treatment patterns, geriatric health status and HER2 testing. This will be beneficial for improving guidance to maximize patient treatment benefit.

Trastuzumab deruxtecan (T-DXd; Enhertu^®) is a medicine approved to treat cancers that produce a protein called HER2 on the surface of cancer cells. T-DXd works by targeting the HER2 protein to deliver chemotherapy directly to cancer cells. Until recently, breast cancers were classified as HER2-positive (high level of HER2 protein on cancer cells) or HER2-negative (very low level/no HER2 protein on cancer cells). T-DXd was approved for treating patients with HER2-positive advanced breast cancer in Europe in 2022. In 2023 the DESTINY-Breast04 clinical trial showed that T-DXd was more effective than current standard chemotherapies, when treating advanced breast cancer patients with low levels of the HER2 protein (historically classified as HER2-negative cancer). This trial led to the approval of T-DXd for treating advanced HER2-low breast cancer, providing a new treatment option for 50­60% of breast cancer patients. More information is needed about T-DXd treatment in the real world (for patients treated in the hospital, rather than in a clinical trial). This article describes the purpose and design of the DESTINY-Breast Respond HER2-low Europe study, which will collect and report more information about how effective T-DXd treatment is in the real world. This is a large study aiming to include 1350 eligible patients from 12 countries across Europe. Patients will report their experience of side effects (such as nausea and vomiting) to improve management of T-DXd treatment and maximize patient benefit. The study will also examine how elderly patients respond to T-DXd treatment, and how HER2 levels are being tested. Clinical Trial Registration: ICH CGP: NCT05945732, registered on 6 July 2023 (ClinicalTrials.gov).

Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer.

PURPOSE: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. EXPERIMENTAL DESIGN: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. RESULTS: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. CONCLUSIONS: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

Febrile Neutropenia in Patients with Solid Tumors Undergoing Intravenous Chemotherapy.

INTRODUCTION: Febrile neutropenia (FN) is a potentially life-threatening complication of systemic chemotherapy (CT) that often requires hospital admission. Delay in diagnosis and treatment are associated with higher morbidity and mortality. OBJECTIVE: We aimed to determine the factors that influence FN episodes outcomes in the emergency room (ER). METHODS: This was a retrospective study of all FN episodes (with a collected blood culture [BC]) that occurred between 2012 and 2016 at our institution. FN was defined as a temperature ≥38°C and an absolute neutrophil count (ANC) <1,000/µL, expected to decrease to <500/µL in the following week. RESULTS: Between 2012 and 2016, there were 173 FN episodes in 153/1,947 patients treated with intravenous CT. Most of these episodes (n = 121, 70%) were diagnosed in the ER, 29 in the outpatient clinic, and 23 as inpatients. In the ER, the median time was 36 min from hospital nurse triage to medical observation, and 52 min from medical observation to complete blood count specimen collection. There was a positive BC in 33 FN episodes, 72% with Gram-negative bacteria. A total of 160 FN episodes led to hospital admission and 13 were treated as outpatients. Mortality associated with the FN episode was 15% and an ANC <100/µL was predictive of increased mortality. CONCLUSION: This study confirms that FN is a serious and common complication of IV CT which must be diagnosed and treated promptly. Profound neutropenia was the only predictive factor of mortality.

Fatal Clostridium septicum febrile neutropenia during adjuvant chemotherapy for early breast cancer.

We report the case of a 76-year-old female patient with early breast cancer (hormone receptor-positive erbb2 amplified) that had started adjuvant chemotherapy with docetaxel, carboplatin and trastuzumab (TCH). Eight days after the first cycle of TCH chemotherapy, the patient was diagnosed with grade 1 oral mucositis, treated conservatively. The next day she started with nausea, vomiting, chills and fever, followed by a generalised tonicoclonic seizure. She presented to the emergency department with fever, hypotension and mild abdominal tenderness. Grade 4 neutropenia (370 µL/mL) and severe metabolic acidosis were documented. An abdominal CT scan documented extensive ischaemic bowel changes, with gas in portal and mesenteric veins, and pneumoretroperitoneum. Despite broad spectrum antibiotics and fluid resuscitation, she died 4 hours after admitted to hospital. Blood cultures collected on hospital admission eventually grew Clostridium septicum bacteria, an extremely rare infection in patient with breast cancer.

ONKOTEV Score as a Predictive Tool for Thromboembolic Events in Pancreatic Cancer-A Retrospective Analysis.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in patients with cancer and causes considerable morbidity and mortality. The risk of VTE is higher in patients with pancreatic cancer and is often associated with treatment delays or interruptions. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing. PATIENTS AND METHODS: We conducted a retrospective study to determine the incidence of VTE and to evaluate the ONKOTEV score as a VTE predictive tool in a population of patients with pancreatic cancer. RESULTS: Between February 2012 and May 2017, 165 patients were included in the study. The median age was 73 years, 45.5% of patients were female, and 55.8% had stage IV disease. Fifty-one patients had a VTE (30.9%); 23.5% had pulmonary embolism, 25.5% had deep venous thrombosis, and 51.0% had visceral VTE (VsT). At a median follow-up time of 6.3 months, cumulative incidence of VTE was less than 10% for ONKOTEV scores 0 or 1 and approximately 40% and 70% for scores 2 and ≥3, respectively. CONCLUSION: The high VTE incidence observed in this study is consistent with prior reports. Patients at high risk for VTE with no increase in hemorrhagic risk should be considered for primary thromboprophylaxis. The ONKOTEV score may stratify VTE risk in patients with pancreatic cancer, with ONKOTEV score ≥2 being associated with a higher VTE occurrence. IMPLICATIONS FOR PRACTICE: Venous thromboembolism (VTE) is a frequent complication of patients with pancreatic cancer and causes considerable morbidity, treatment delays or interruptions, and mortality. Thromboprophylaxis is not used routinely in ambulatory patients. Tools to stratify the risk of VTE are important to help select patients who may benefit from thromboprophylaxis. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing. In this patient series, ONKOTEV score ≥2 was associated with high VTE occurrence and may stratify VTE risk in patients with pancreatic cancer, suggesting that ONKOTEV can be considered to select patients with pancreatic cancer for primary thromboprophylaxis.

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study.

BACKGROUND: Ovarian function suppression (OFS) with tamoxifen or aromatase inhibitors (AIs) improves disease-free survival in premenopausal women with breast cancer, mostly in those at higher risk of recurrence. However, its real-world use and impact remain poorly understood. PATIENTS AND METHODS: This is a multicenter retrospective cohort study of premenopausal women with stage I to III hormone receptor-positive breast cancer diagnosed from 2006 to 2015 that aimed to look at the uptake and effectiveness of the addition of OFS to backbone endocrine therapy (tamoxifen or AI). To deal with confounding, we used both multivariate modeling and propensity score matching. RESULTS: Of 1717 eligible patients, 17.1% were treated with OFS. There was a substantial increase of use of OFS over time, especially from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). In a multivariate model, only younger age and year of diagnosis ≥ 2014 were associated with OFS utilization (both P < .001). With a median follow-up of 38 months (P25-P75, 19.6-66.4 months), patients receiving OFS had a better overall survival than those not receiving OFS (adjusted hazard ratio, 0.44; 95% confidence interval, 0.19-0.96; absolute benefit at 5 years, 2.1% [95.3% vs. 93.2% in those not receiving OFS]). A similar benefit was identified using propensity score matching. CONCLUSIONS: In the real-world setting, there was an increase in the use of OFS after 2014. After 2014, one-quarter of premenopausal women received adjuvant OFS, of which more than 30% received it in combination with an AI. In this study, the use of adjuvant OFS was associated with an overall survival benefit.

Acute reversible toxic encephalopathy during capecitabine and oxaliplatin treatment.

INTRODUCTION: Capecitabine is a fluoropyrimidine commonly used in the treatment of colorectal cancer which may cause central nervous system toxicity, namely cerebellar dysfunction. CASE REPORT: We describe a 77-year-old man undergoing adjuvant treatment of colon cancer with capecitabine and oxaliplatin who presented with acute cerebellar ataxia and encephalopathy that progressed to coma. Diagnosis of toxic encephalopathy was made after the exclusion of alternative causes of neurological dysfunction and complete resolution of clinical findings with permanent discontinuation of chemotherapy. DISCUSSION: When patients with cancer develop symptoms and signs of central nervous dysfunction, metabolic and infectious causes plus tumor involvement of central nervous system must be sought. However, chemotherapy may also cause toxicity to the central nervous system. Capecitabine is no exception, although cerebellar dysfunction is rarely reported. CONCLUSION: Although rare, capecitabine-induced encephalopathy may be severe and physicians should be aware of this possible side effect.

Does Hypoxic Response Mediate Primary Resistance to Sunitinib in Untreated Locally Advanced Breast Cancer?

BACKGROUND: The antiangiogenic drug sunitinib has never been evaluated as single agent in untreated breast cancer patients. OBJECTIVE: We aimed to characterize the activity of sunitinib, alone and with docetaxel, in untreated locally advanced or operable breast cancer and to uncover the mechanisms of response. METHOD: Patients were treated with an upfront window of sunitinib followed by four cycles of sunitinib plus docetaxel. Response, resistance and toxicity were evaluated according to standard clinical parameters, magnetic resonance imaging, positron emission tomography, standard pathology characterization, molecular pathology and gene expression profiling. RESULTS: Twelve patients were included. We detected primary resistance to sunitinib in the upfront window in untreated breast cancer, as evidenced by four non-responding patients. At surgery, five patients had viable tumor in the breast and axilla, four had viable tumor cells in the breast alone and three were taken off study and thus not evaluated, due to unacceptable toxicity. Early functional imaging was useful in predicting response. There were no clinical complete responses. Comparison of tumor gene expression profiling data between early responders and non-responders allowed us to identify the up-regulation of VEGF and angiogenic pathways in non-responders. Specifically, in tumors resistant to single-agent sunitinib we detected a transcriptional response to hypoxia characterized by over-expression of several HIF1α target genes. CONCLUSION: In this report of single-agent sunitinib treatment in untreated localized breast cancer patients, we found evidence of primary resistance to sunitinib, likely mediated by up-regulation of hypoxia responsive genes.

Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional Portuguese cohort study.

BACKGROUND: A contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. METHODS: Retrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. RESULTS: Among patients with stage I-III breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2- tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2- received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. CONCLUSIONS: Overall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions.

The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer--a systematic review.

INTRODUCTION: This study aimed at evaluating the overall survival (OS) gain associated with human epidermal growth factor receptor 2 (HER2)-directed therapies in patients with metastatic breast cancer (mBC). METHODS: A bibliographic search was conducted in PubMed and Cochrane databases. Only phase III randomized controlled trials (RCTs) including HER2-positive (HER2+) mBC patients were included in this review. OS was defined as time from randomization until the occurrence of death from any cause. Studies have been grouped according to the line of treatment, i.e., first-line or second-line or beyond. RESULTS: Nineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783-92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461-71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the second-line setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533-43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783-91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585-92, 2012)). CONCLUSIONS: HER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2+ mBC. The triple combination of docetaxel, pertuzumab and trastuzumab is associated with a survival extent of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 14 years ago.

Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO.

BACKGROUND: Oncologic treatment in elderly patients is challenging, due to comorbidities, often impaired organ function, limited clinical trial evidence, inadequate guidelines and no consistent 'elderly' definition. We report exploratory sub-analyses of safety and efficacy in elderly patients, defined as ⩾ 65years old, in AVastin And DOcetaxel (AVADO) receiving first-line bevacizumab plus docetaxel for metastatic breast cancer (mBC). PATIENTS AND METHODS: Patients with HER2-negative, locally recurrent or mBC were randomised to 3-weekly docetaxel (100mg/m(2)) with placebo, bevacizumab 7.5mg/kg or bevacizumab 15 mg/kg, for 9 cycles or until disease progression or unacceptable toxicity. Patients had no prior chemotherapy for mBC. RESULTS: Progression-free survival (PFS) was increased with bevacizumab in the elderly subpopulation (n=127), the effect being greater with higher dose (hazard ratio=0.63 [95% confidence interval (CI) 0.383-1.032] versus 0.76 [95% CI: 0.46-1.262], respectively). PFS was numerically similar in the elderly and overall populations, but the former failed to achieve statistical significance. Overall response rates for docetaxel plus placebo, bevacizumab 7.5mg/kg and 15 mg/kg were 44.7%, 36.6% and 50.0%, respectively. Effects on survival were not statistically significant. Bevacizumab was well tolerated in elderly patients, the most common adverse effects were neutropenia and febrile neutropenia; there was no excess of grade⩾3 cardiovascular events. There was no clear correlation between baseline hypertension and its development during study treatment. CONCLUSIONS: In this exploratory sub-analysis in AVADO, bevacizumab plus docetaxel showed efficacy in elderly patients similar to the overall study population. There were no unexpected safety signals in patients aged 65 years or older.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.

Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence.

INTRODUCTION: Human mammaglobin (hMAM) mRNA is a sensitive and specific marker of breast cancer cells. We evaluated if hMAM mRNA detection in serial peripheral blood samples from non-metastatic breast cancer patients predicts for disease recurrence. METHODS: Patients scheduled for adjuvant or neoadjuvant chemotherapy were eligible. Serial blood samples were collected up to 5 years, the first before (neo)adjuvant chemotherapy. hMAM gene expression was analysed by RT-PCR. Specificity was evaluated in blood samples from healthy volunteers. A total of 321 patients were included. RESULTS: The incidence of pre-chemotherapy hMAM-positive samples was similar in patients who latter experienced cancer recurrence (22.4%) and those who remained disease-free (17.9%; P = 0.46). Similarly, the mean number of positive follow-up samples was similar in both groups (0.15 +/- 0.22 and 0.13 +/- 013; P = 0.29). Furthermore, there was no difference in disease-free (P = 0.63) or overall survival (P = 0.57) in patients with and without positive baseline samples or between patients whose follow-up samples were always hMAM negative and those with at least one positive sample. Multivariate survival analysis confirmed that hMAM mRNA detection before or after (neo)adjuvant chemotherapy was not predictive of recurrence. DISCUSSION: There is no evidence that hMAM mRNA detection at diagnosis or during follow-up predicts for breast cancer recurrence.

[High-dose chemotherapy and stem-cell in patients with breast cancer]. / Quimioterapia intensiva comsuporte hematopoiético autólogoem doentes com carcinoma da mama.

BACKGROUND: The treatment of breast cancer patients with high-dose chemotherapy and stem-cell support is still highly controversial. The elucidation of its clinical benefit awaits the maturation of on-going clinical trials. METHODS: Patients with chemotherapy-sensitive metastatic or locally advanced disease and patients with stage II/III disease and at least four positive axillary lymph nodes in the initial surgical specimen were eligible for transplantation. RESULTS: Fifty-five women underwent transplantation between 1994 and 2000. For the 19 women with metastatic disease, the median time to progression was seven month and survival 28 months. Only two patients are progression-free, at 48 and 77 months, both with supraclavicular and/or cervical lymph node-only disease. For the 36 women with stage II/III disease, the median time to progression and survival were both 65 months -19 are alive, 18 disease-free. Among the subgroup of 23 patients with 10 or more positive axillary nodes, the five-year event-free survival was 57%. CONCLUSION: The clinical benefit of stem-cell transplantation for metastatic breast cancer is limited since the time to progression and survival after transplantation is similar to those reported in patients with newly diagnosed metastases and treated with conventional-dose chemotherapy. However, in patients with high-risk stage II/III disease the time to progression is longer than that reported for similar patients treated with conventional systemic treatment. These results are similar to previous reports in the literature.