Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.

BACKGROUND: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known. METHODS: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings. RESULTS: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed. CONCLUSIONS: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer.

PURPOSE: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. METHODS: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. CONCLUSION: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. CLINICALTRIALS: gov Identifier: NCT00083031. Date of Registration: May 17, 2004.

Second primary non-breast cancers in young breast cancer survivors.

PURPOSE: We evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors. METHODS: This study included participants of the Young Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments. RESULTS: Among 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models. CONCLUSION: In this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors.

Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial.

Importance: Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective: To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants: A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions: Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. Results: A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance: Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02927249.

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial.

BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011). INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FUNDING: Genentech.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

Nodal Positivity in Early-Stage Triple-Negative Breast Cancer: Implications for Preoperative Immunotherapy.

BACKGROUND: Adding pembrolizumab to preoperative chemotherapy improves event-free survival in patients with early-stage triple-negative breast cancer (TNBC). However, owing to potential toxicities, the risk-benefit ratio of pembrolizumab must be considered. There is consensus that the addition of immunotherapy should be recommended in node-positive patients. This study is undertaken to determine nodal positivity rates in patients with TNBC presenting with cT1-2N0 disease undergoing upfront surgery and to evaluate the utility of axillary ultrasound and biopsy in the setting of a negative clinical examination. PATIENTS AND METHODS: Patients with cT1-2N0 TNBC undergoing upfront surgery were identified from our institutional database (January 2016-February 2021; n = 343) and from the National Cancer Database (NCDB) (n = 46,015). Pathologic nodal status was determined. A second cohort of patients with cT1-T2 TNBC with a negative clinical examination was defined in our institutional database (n = 499), and utilization of axillary ultrasound was examined. RESULTS: For patients undergoing upfront surgery, pathologically positive nodes were found in 14.6% patients of our institutional cohort: 9.4% cT1a/b, 14.9% cT1c, and 20.8% cT2 tumors. In the NCDB cohort, 13.7% patients were node positive: 4.9% cT1a/b, 11.4% cT1c, and 19.7% cT2 tumors. For patients with a normal clinical examination undergoing axillary ultrasound, 7.5% of cT1c and 8.7% of cT2 had suspicious nodes biopsied and confirmed positive for metastasis. CONCLUSIONS: Pathologic node-positive disease is found in > 10 and 20% patients with cT1cN0 and cT2N0 TNBC, respectively. Axillary ultrasound can be used to identify patients presenting with a normal clinical examination for whom preoperative pembrolizumab should be considered.

CDK4/6 inhibition triggers anti-tumour immunity.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

Exploring anxiety as an influencing factor of the impact of exercise and mind-body prehabilitation on cognitive functioning among women undergoing breast cancer surgery.

OBJECTIVE: The purpose of this secondary analysis was to describe the prevalence of anxiety, depression, and perceived stress among women newly diagnosed with breast cancer and the impact of baseline and changes in anxiety on cognitive functioning following exercise and mind-body prehabilitation interventions. METHODS: The sample consisted of 49 women with newly diagnosed breast cancer (stages I-III) who planned to undergo breast cancer surgery at two academic cancer centers. Participants were randomized to receive an exercise or mind-body prehabilitation intervention between the time of diagnosis and breast cancer surgery. Participants completed self-report measures of anxiety, depression (HADS), perceived stress, and cognitive functioning (EORTC-QLQ-C30) at study enrollment and prior to surgery (post-intervention). The relationships between change in cognitive functioning and change in anxiety among all participants were estimated using linear regression modeling. RESULTS: A significant proportion of women with newly diagnosed breast cancer had clinically significant anxiety (34.0%). Greater anxiety was moderately associated with worse cognitive functioning (r = -0.33) at baseline. Linear modeling found that changes in cognitive functioning and anxiety were inversely related: Each one-unit decrease in anxiety was associated with a two-unit improvement in cognitive function (p = .06). CONCLUSIONS: Anxiety was common in women with newly diagnosed breast cancer and was related to worse cognitive functioning. Assessment of anxiety at the time of diagnosis may allow for earlier anxiety management and subsequent improvement in cognitive functioning.

Efficacy of neoadjuvant chemotherapy in male breast cancer compared with female breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard for many females with breast cancer (FBC). The efficacy of NAC in male breast cancer (MaBC) is unclear. The aim of this study was to compare proportions of pathologic complete response (pCR) between MaBC and FBC by tumor subtype (TS). METHODS: MaBC and FBC treated with NAC between 2010 and 2016, with known TS, were evaluated from the National Cancer Database. Proportions of pCR (ypT0/Tis ypN0) were compared between sexes within TS by Fisher test. Multivariable logistic regression assessed the independent association of sex with pCR. Overall survival (OS) was estimated by Kaplan-Meier. RESULTS: A total of 385 MaBC and 68,065 FBC were included. Median time from initiation of NAC to surgery was 143 days in MaBC and 148 days in FBC. Proportions of pCR in MaBC and FBC by TS were: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-): 4.9% vs 9.7%, p = .01; HR+/HER2+: 16.1% vs 33.6%, p < .001; HR-/HER2+: 44.0% vs 53.2%, p = .42; and HR-/HER2-: 21.4% vs 32.1%, p = .18, respectively. FBC had twice the odds of pCR than MaBC (adjusted odds ratio, 2.0; 95% CI, 1.5-2.8; p < .001). Five-year OS for MaBC with pCR vs not was 90% vs 64.7%; p = .02. Five-year OS for FBC with pCR vs not was 91.9% vs 75.3%; p < .01. CONCLUSIONS: Proportions and odds of pCR to NAC were numerically lower in MaBC compared with FBC for each TS and statistically significant for HR+/HER2- and HR+/HER2+. The independent association of sex with pCR was confirmed in multivariable analysis. pCR is prognostic in both MaBC and FBC.

The feasibility of using an autologous GM-CSF-secreting breast cancer vaccine to induce immunity in patients with stage II-III and metastatic breast cancers.

PURPOSE: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer. METHODS: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III). RESULTS: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells. CONCLUSION: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009).

Perceptions of patients and medical oncologists toward biospecimen donation in the setting of abnormal breast imaging findings.

PURPOSE: We sought to understand the attitudes of individuals with abnormal breast imaging findings prompting a diagnostic breast biopsy toward donation of blood, excised tissue, or percutaneous biospecimens for research, and to understand medical oncologists' attitudes toward research biospecimen collection in this population. METHODS: We included individuals who presented to a single academic medical center for a clinically indicated, image-guided, percutaneous breast biopsy. We administered a survey prior to knowledge of biopsy results to assess willingness to consider, entirely for research purposes, donating blood or excess excised breast tissue, or having additional biospecimens (AB) obtained during a clinically indicated percutaneous biopsy. We also surveyed breast medical oncologists from National Cancer Institute-designated cancer centers to assess attitudes toward approaching patients for biospecimen research. RESULTS: Overall, 53/63 patients responded to the survey; 70% would consider donating blood, 85% would consider donating excess excised breast tissue, and 32% would consider having AB obtained during a clinically indicated biopsy. Main motivating factors for considering AB included contributing to scientific knowledge and return of study or biopsy results, whereas anxiety and the potential discomfort were the main dissuading factors. Among 191 medical oncologists, most were very comfortable (59.2%), or somewhat comfortable (32.5%) asking patients to have AB obtained during a clinically indicated breast biopsy. Medical oncologists reported hesitancy to refer a patient for AB due to potential pain/discomfort, and other procedure risks. CONCLUSIONS: Only one-third of individuals with breast imaging findings would consider consenting to AB during a diagnostic biopsy, whereas most were open to donating blood or excess excised breast tissue. Most medical oncologists would be comfortable asking patients to have AB obtained during the biopsy. Understanding patients' and oncologists' baseline attitudes may inform the design and approach to breast biospecimen-based research.

Expanding the Staging Criteria for T1-2N0 Hormone-Receptor Positive Breast Cancer Patients Enrolled in TAILORx.

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th edition pathologic prognostic staging (PPS) incorporates anatomic and biologic factors. The OncotypeDX Breast Recurrence Score (RS) was included based on the initial report of the TAILORx trial, with T1-2N0 hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients who had a RS < 11 staged as PPS 1A. This study examined whether the RS criteria for PPS 1A can be further expanded using patients enrolled in the TAILORx trial. METHODS: The TAILORx trial enrolled 10,273 HR+HER2- T1-2N0 patients. Those with incomplete HR-status/grade and T3 disease were excluded for analysis. The recurrence-free interval (RFI) was compared between the patients who did and those who did not fall into the current PPS 1A category using the Kaplan-Meier method. RESULTS: The study enrolled 9535 patients for analysis. The RS was < 11 in 16.1%, 11-17 in 35.9%, 18-25 in 32.4%, and > 25 in 15.6% of the patients. The majority (91.2%) of the patients (including all the T1N0 patients regardless of RS) were PPS 1A, and 8.8% were not-PPS 1A. The median follow-up time was 95 months. The PPS 1A patients had an 8-year RFI of 94.2%, which was similar to that of the patients with a RS of 11-17 who were not-PPS 1A (91.7%; p = 0.07) and better than that of the patients with a RS ≥ 18 who were not-PPS 1A (85.4% for a RS of 18-25, 76.0% for a RS > 25; both p < 0.01). Similar RFI trends were seen in patients who received endocrine therapy or chemotherapy followed by endocrine therapy. CONCLUSIONS: Patients with T1-2N0 HR+HER2- breast cancer and a RS < 18 have an RFI similar to that of patients staged as PPS 1A by the current AJCC staging system, regardless of treatment, suggesting that the criteria for PPS 1A can be expanded to include a RS < 18.

Exploring the impact of exercise and mind-body prehabilitation interventions on physical and psychological outcomes in women undergoing breast cancer surgery.

PURPOSE: To compare the impact of exercise and mind-body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer. METHODS: The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind-body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models. RESULTS: Mind-body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind-body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind-body: average change = -2.59, p = 0.05, d = 0.29), while mind-body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67). CONCLUSIONS: Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind-body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012.

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

BACKGROUND: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. METHODS: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. FINDINGS: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). INTERPRETATION: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Perceptions of patients with early stage breast cancer toward research biopsies.

BACKGROUND: The objective of this study was to describe the perspective of patients with early breast cancer toward research biopsies. The authors hypothesized that more patients at academic sites than at community-based sites would be willing to consider these procedures. METHODS: In total, 198 patients with early stage breast cancer were recruited from 3 academic centers (n = 102) and from 1 community oncology practice (n = 96). The primary objective was to compare the proportion of patients willing to consider donating excess tissue biospecimens from surgery, from a clinically indicated breast biopsy, or from a research purposes-only biopsy (RPOB) between practice types. RESULTS: Most patients (93% at academic sites, 94% at the community oncology site) said they would consider donating excess tissue from surgery for research. One-half of patients from academic or community sites would consider donating tissue from a clinically indicated breast biopsy. On univariate analysis, significantly fewer patients from academic sites would consider an RPOB (22% at academic sites, 42% at the community site; P = .003); however, this difference was no longer significant on multivariate analysis (P = .96). Longer transportation times and unfavorable prior experiences were associated with less willingness to consider an RPOB on multivariate analysis. Significantly fewer patients from academic sites (14%) than from the community site (35%) would consider a research biopsy in a clinical trial (P = .04). Contributing to scientific knowledge, return of results, and a personal request by their physician were the strongest factors influencing patients' willingness to undergo research biopsies. CONCLUSIONS: The current results rejected the hypothesis that more patients with early breast cancer at academic sites would be willing to donate tissue biospecimens for research compared with those at community oncology sites. These findings identify modifiable factors to consider in biobanking studies and clinical trials.

Impact of Cancer History on Outcomes Among Hospitalized Patients with COVID-19.

BACKGROUND: Early reports suggested increased mortality from COVID-19 in patients with cancer but lacked rigorous comparisons to patients without cancer. We investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death in hospitalized patients with COVID-19. PATIENTS AND METHODS: We identified patients with a history of cancer admitted to two large hospitals between March 13, 2020, and May 10, 2020, with laboratory-confirmed COVID-19 and matched them 1:2 to patients without a history of cancer. RESULTS: Men made up 56.2% of the population, with a median age of 69 years (range, 30-96). The median time since cancer diagnosis was 35.6 months (range, 0.39-435); 80% had a solid tumor, and 20% had a hematologic malignancy. Among patients with cancer, 27.8% died or entered hospice versus 25.6% among patients without cancer. In multivariable analyses, the odds of death/hospice were similar (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.65-1.82). The odds of intubation (OR, 0.46; 95% CI, 0.28-0.78), shock (OR, 0.54; 95% CI, 0.32-0.91), and intensive care unit admission (OR, 0.51; 95% CI, 0.32-0.81) were lower for patients with a history of cancer versus controls. Patients with active cancer or who had received cancer-directed therapy in the past 6 months had similar odds of death/hospice compared with cancer survivors (univariable OR, 1.31; 95% CI, 0.66-2.60; multivariable OR, 1.47; 95% CI, 0.69-3.16). CONCLUSION: Patients with a history of cancer hospitalized for COVID-19 had similar mortality to matched hospitalized patients with COVID-19 without cancer, and a lower risk of complications. In this population, patients with active cancer or recent cancer treatment had a similar risk for adverse outcomes compared with survivors of cancer. IMPLICATIONS FOR PRACTICE: This study investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death or hospice admission in hospitalized patients with COVID-19. Active cancer, systemic cancer therapy, and a cancer history are not independent risk factors for death from COVID-19 among hospitalized patients, and hospitalized patients without cancer are more likely to have severe COVID-19. These findings provide reassurance to survivors of cancer and patients with cancer as to their relative risk of severe COVID-19, may encourage oncologists to provide standard anticancer therapy in patients at risk of COVID-19, and guide triage in future waves of infection.

Prospective Study Testing a Simplified Paclitaxel Premedication Regimen in Patients with Early Breast Cancer.

BACKGROUND: In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-paclitaxel regimen. PATIENTS, MATERIALS, AND METHODS: In this prospective, single-arm study, patients who completed four cycles of DD-AC for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3-4 HSRs. RESULTS: Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%-20.0%) patients had any-grade HSRs, for a total of 22 (4.5%; 3.1%-6.4%) HSRs over 486 paclitaxel cycles. Any-grade HSRs occurred in 1.6% (0.3%-5.0%), 6.5% (3.3%-11.3%), 7.4% (3.9%-12.5%), and 2.6% (0.7%-6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%-2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any-grade HSRs occurred in 2.7% (3/111; 0.7%-6.8%) and 0.9% (1/109; 0.05%-4.3%) of patients in cycle 3 and 4, respectively. CONCLUSION: Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose-dense paclitaxel if HSRs are not observed during cycles 1 and 2. IMPLICATIONS FOR PRACTICE: Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care.