Background
This study explores the incidence of patient‐reported major toxicity—symptoms rated “moderate,” “severe,” or “very severe”—for chemotherapy regimens commonly used in early breast cancer.
...Patients and Methods
Female patients aged 21 years or older completed a validated Patient‐Reported Symptom Monitoring instrument and rated 17 symptoms throughout adjuvant or neoadjuvant chemotherapy. Fisher's exact tests compared differences in percentages in symptom ratings, and general linear regression was used to model the incidence of patient‐reported major toxicity.
Results
In 152 patients, the mean age was 54 years (range, 24–77), and 112 (74%) were white; 51% received an anthracycline‐based regimen. The proportion of patients rating fatigue, constipation, myalgia, diarrhea, nausea, peripheral neuropathy, and swelling of arms or legs as a major toxicity at any time during chemotherapy varied significantly among four chemotherapy regimens (p < .05). The mean (SD) number of symptoms rated major toxicities was 6.3 (3.6) for anthracycline‐based and 4.4 (3.5) for non‐anthracycline‐based regimens (p = .001; possible range, 0–17 symptoms). Baseline higher body mass index (p = .03), patient‐reported Karnofsky performance status ≤80 (p = .0003), and anthracycline‐based regimens (p = .0003) were associated with greater total number of symptoms rated major toxicities (alternative model: chemotherapy duration, p < .0001). Twenty‐six percent of dose reductions (26 of 40), 75% of hospitalizations (15 of 20), and 94% of treatment discontinuations (15 of 16) were in anthracycline‐based regimens.
Conclusion
Capturing multiple toxicity outcomes throughout chemotherapy enables oncologists and patients to understand the range of side effects as they discuss treatment efficacies. Continuous symptom monitoring may aid in the timely development of interventions that minimize toxicity and improve outcomes.
Implications for Practice
This study investigated patient‐reported toxicities for 17 symptoms recorded prospectively during adjuvant and neoadjuvant chemotherapy regimens for early breast cancer. An analysis of four commonly used chemotherapy regimens identified significant differences among regimens in both individual symptoms and total number of symptoms rated moderate, severe, or very severe. Longer chemotherapy regimens, such as anthracycline‐based regimens followed by paclitaxel, had higher proportions of symptoms rated major toxicities. The inclusion of patient perspectives on multiple toxicity outcomes at the same time at multiple time points during chemotherapy has the potential for improving patient‐provider communication regarding symptom management, patient satisfaction, and long‐term clinical outcomes.
摘要
背景。本研究探索了在常用于治疗早期乳腺癌的化疗方案中患者报告的主要毒性(即被评为“中度”、“重度”或“极重度”的症状)的发生率。
患者和方法。年满 21 岁或以上的女性患者填写一份经验证的患者报告的症状监测文件并对辅助或新辅助化疗期间的 17 个症状进行评级。Fisher's精确检验对症状评级百分比之间的差异进行比较，一般线性回归用于模拟患者报告的主要毒性的发生率。
结果。在 152 名患者中，平均年龄为 54 岁(范围介于 24–77 岁之间)，112 名患者 (74%) 为白种人；51% 的患者接受蒽环类方案治疗。在化疗期间的任何时间将疲劳、便秘、肌痛、腹泻、恶心、周围神经病变以及手臂或腿部肿胀评为主要毒性的患者的比例在 4 个化疗方案中显著不同 (p < 0.05)。在蒽环类方案和非蒽环类方案中，被评为主要毒性的症状的平均数 (SD) 分别为 6.3 (3.6) 和 4.4 (3.5)(p = 0.001；可能的范围，0–17 个症状)。基线较高的体质量指数 (p = 0.03)、患者报告的 Karnofsky 体力状态 ≤80 (p = 0.000 3) 以及蒽环类方案 (p = 0.000 3) 与被评为主要毒性的症状的总数较高相关(替代模式:化疗持续时间，p < 0.000 1)。在蒽环类方案中，剂量减少占 26%(40 名患者中的 26 名患者)，住院治疗占 75%(20 名患者中的 15 名患者)，治疗中断占 94%(16 名患者中的 15 名患者)。
结论。获取化疗过程中的多种毒性结果，可令肿瘤学家和患者在讨论治疗有效性时了解副作用的范围。持续的症状监测可能有助于及时地制定可以最大限度地减少毒性并改进预后的干预措施。
《肿瘤学家》
实践意义:本研究调查了患者报告的早期乳腺癌辅助和新辅助化疗方案中前瞻性记录的 17 个症状的毒性。针对 4 个常用化疗方案的分析在单项症状和被评为“中度”、“重度”或“极重度”的症状的总数方面确定了方案之间的显著差异。在较长的化疗方案中，如后续采用紫杉醇治疗的蒽环类方案，被评为主要毒性的症状占有较高的比例。同时，在化疗期间的多个时间点加入患者关于多种毒性结果的看法，这可能会改进患者和医疗服务提供者之间有关症状管理、患者满意度以及长期临床预后的沟通。
This article focuses on the incidence of patient‐reported major toxicity for chemotherapy regimens commonly used in breast cancer, especially considering the need for patient‐centered assessments of treatment tolerability as an important complement to the NCI's CTCAE.
Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are ...unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials.
Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.
Background
In the current study, the authors investigated the incidence of moderate to severe chemotherapy‐induced peripheral neuropathy (CIPN) for chemotherapy regimens commonly used in current ...clinical practice for the treatment of patients with early breast cancer. Patient‐reported and clinician‐assessed CIPN severity scores were compared, and risk factors for CIPN severity were identified.
Methods
Patients completed a Patient‐Reported Symptom Monitoring form and oncologists completed a Common Terminology Criteria for Adverse Events form. CIPN reports were collected prospectively during regularly scheduled infusion visits throughout the duration of chemotherapy.
Results
The sample included 184 women with a mean age of 55 years; approximately 73% were white. The 4 chemotherapy regimens used were doxorubicin and cyclophosphamide plus paclitaxel (60 patients); docetaxel and cyclophosphamide (50 patients); docetaxel, carboplatin, and anti–human epidermal growth factor receptor 2 (HER2) (24 patients); and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin (18 patients). All patients treated with doxorubicin and cyclophosphamide plus paclitaxel and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin received paclitaxel; all patients treated with docetaxel and cyclophosphamide and docetaxel, carboplatin, and anti‐HER2 received docetaxel. The chemotherapy dose was reduced in 52 patients (28%); in 15 patients (29%), this reduction was due to CIPN. Chemotherapy was discontinued in 26 patients (14%), 8 because of CIPN. Agreement between patient‐reported and clinician‐assessed CIPN severity scores was minimal (weighted Cohen kappa, P = .34). Patient‐reported moderate to severe CIPN was higher for paclitaxel (50%) compared with docetaxel (17.7%) (P < .001). Pretreatment arthritis and/or rheumatism (relative risk RR, 1.58; 95% CI, 1.06‐2.35 P = .023) and regimens containing paclitaxel (RR, 2.88; 95% CI, 1.72‐4.83 P < .0001) were associated with higher CIPN severity. Being married (RR, 0.57; 95% CI, 0.37‐0.887 P = .01) was found to be associated with lower CIPN severity.
Conclusions
The discrepancy between patient‐reported and clinician‐assessed CIPN underscores the need for both patient and clinician perspectives regarding this common, dose‐limiting, and potentially disabling side effect of chemotherapy.
The severity of patient‐reported chemotherapy‐induced peripheral neuropathy (CIPN) varies by the regimen used in current clinical practice for the treatment of early breast cancer. The discrepancy between patient‐reported and clinician‐assessed CIPN underscores the need for both patient and clinician perspectives on this common, dose‐limiting, and potentially disabling side effect of chemotherapy.
Abstract
Background
Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant ...bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer.
Methods
Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided.
Results
A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval CI = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%).
Conclusions
We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
Background
The National Cancer Institute's Patient‐Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, collected alongside the clinician‐reported Common Terminology ...Criteria for Adverse Events, enables comparisons of patient and clinician reports on treatment toxicity.
Methods
In a multisite study of women receiving chemotherapy for early‐stage breast cancer, symptom reports were collected on the same day from patients and their clinicians for 17 symptoms; their data were not shared with each other. The proportions of moderate, severe, or very severe patient‐reported symptom severity were compared with the proportions of clinician‐rated grade 2, 3, or 4 toxicity. Patient‐clinician agreement was assessed via κ statistics. Chi‐square tests investigated whether patient characteristics were associated with patient‐clinician agreement.
Results
Among 267 women, the median age was 58 years (range, 24‐83 years), and 26% were nonwhite. There was moderate scoring agreement (κ = 0.413‐0.570) for 53% of symptoms, fair agreement for 41% (κ = 0.220‐0.378), and slight agreement for 6% (κ = 0.188). For example, patient‐reported and clinician‐rated percentages were 22% and 8% for severe or very severe fatigue, 41% and 46% for moderate fatigue, 32% and 39% for mild fatigue, and 6% and 7% for none. Clinician severity scores were lower for nonwhite patients in comparison with white patients for peripheral neuropathy, nausea, arthralgia, and dyspnea.
Conclusions
Although clinician reporting of symptoms is common practice in oncology, there is suboptimal agreement with the gold standard of patient self‐reporting. These data provide further evidence supporting the integration of patient‐reported outcomes into oncological clinical research and clinical practice to improve monitoring of symptoms as well as timely interventions for symptoms.
Although clinician reporting of symptoms is common practice in oncology, there is suboptimal agreement with the gold standard of patient self‐reporting. These data provide further evidence supporting the integration of patient‐reported outcomes into oncological clinical research and clinical practice to improve monitoring of symptoms as well as timely interventions for symptoms.
A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit.
...To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone.
In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019.
The adjuvant chemotherapy regimen was selected by the treating physician.
Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival IDFS).
Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error SE, 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%).
The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.
ClinicalTrials.gov identifier: NCT00310180.
Purpose
Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk ...factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.
Methods
SWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.
Results
Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (
p
= 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (
p
< 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.
Conclusion
ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.
Clinical trial number
NCT00127205
Registration date
July 2005
Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most ...patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1.
This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in ...melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses.
We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930).
Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets.
Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.
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