Preparing Hematology/Oncology Fellows for Success: Implementing an Annual Career Development and Research Retreat.

Multiple factors, including job satisfaction, personality traits, and training experiences, influence the career trajectory of hematology/oncology fellows. In an effort to expose hematology/oncology fellows to (1) the various careers in oncology, (2) a diverse group of speakers for future mentorship, and (3) research opportunities, and grant writing experience, we established an annual career development and research retreat. During the retreat, we engaged speakers who covered a range of career trajectories, including academic, private practice, industry, government, and administrative paths. We introduced clinicians and researchers with a track record of providing top-notch mentorship to fellows with aligning interests and detailed research opportunities and grant writing. The sessions were led by senior fellows, and we adopted an in-person and virtual hybrid model to allow speakers from various institutions to participate. Feedback from participants, as gathered through surveys, indicated positive responses: all respondents reported that this retreat was "extremely" or "very helpful," and a majority expressed their intent to pursue academic careers. The curriculum and structure of this retreat may help to inform the development of fellowship career development and research retreats at other institutions.

Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i. METHODS: We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. RESULTS: Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months-NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE). CONCLUSIONS: Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.

Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors.

INTRODUCTION: Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. MATERIALS AND METHODS: This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). RESULTS: Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. CONCLUSION: Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. IMPLICATIONS FOR PRACTICE: High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Percutaneous Image-Guided Core Needle Biopsy of Neuroendocrine Tumors: How Common Is Intraprocedural Carcinoid Crisis?

PURPOSE: To retrospectively evaluate the incidence of carcinoid crisis, other complications, and physiologic disturbances during percutaneous image-guided core needle biopsy of neuroendocrine tumors (NETs) in the lung and the liver. MATERIALS AND METHODS: Between January 2010 and January 2020, 106 computed tomography (CT) or ultrasound (US)-guided core needle biopsies of lung and liver NETs were performed in 95 consecutive adult patients. The mean age was 64 ± 13 years, and 48% were female. The small bowel was the most common primary site (33%, 31/95), and 32 (34%) patients had pre-existing symptoms of carcinoid syndrome. The mean tumor size was 3.2 ± 2.6 cm, and mean number of passes was 3.4 ± 1.6. A 17/18-gauge needle was used in 91% (96/106) of the biopsies. Thirteen (12%) patients received either outpatient or prophylactic octreotide. RESULTS: No patients experienced carcinoid crisis or needed octreotide, inotropes, vasopressors, or resuscitation. A single biopsy procedure (0.9%, 1/106) was complicated by bleeding that required angiographic hepatic artery embolization. Changes in pre-biopsy- versus post-biopsy systolic blood pressure and heart rate were -1.6 mm Hg (P = .390) and 0.6 beat/min (P = .431), respectively. Tumor functional status, overall tumor burden, and the elevation of neuroendocrine markers were not associated with intraprocedural physiologic disturbances. There were 4 minor complications (0.4%, 4/106) associated with the biopsy procedure that were not attributed to hormone excretion from tumor manipulation. CONCLUSIONS: Percutaneous image-guided core biopsy of NETs is safe, with low complication rate and no definite carcinoid crisis in the current cohort.

The Role of Perioperative Systemic Therapy in Localized Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. OBJECTIVES: We aimed to evaluate the benefit of PST compared to surgery alone (SA) in patients with localized PanNEN. METHOD: We selected patients with stages I-III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. RESULTS: Four thousand eight hundred and ninety-two patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age <65 years, community medical facilities, grade 3 tumor, tumor in the pancreatic head, T34 tumor, and N1 tumor. Three hundred and one PST patients were matched with 301 SA patients. In the matched cohort, the PST group had significantly shorter overall survival (OS) compared to the SA group (median overall both not reached, p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (hazard ratio [HR] 1.45, 95% CI 1.11-1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved OS in grades 1-2 PanNEN (HR 2.03, 95% CI 1.31-3.16, p = 0.002). CONCLUSIONS: PST stratified by grade and neoadjuvant or adjuvant therapy compared to SA was not associated with improved OS in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.

OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic-based dosing of irinotecan, oxaliplatin, and capecitabine as first-line therapy for patients with advanced small bowel adenocarcinoma.

BACKGROUND: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first-line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype-based dosing could optimize tolerability. METHODS: Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2-15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). RESULTS: A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41-77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%-56%), with a median progression-free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype. CONCLUSIONS: UGT1A1 genotype-directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3-drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494-501. © 2017 American Cancer Society.

Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32.

BACKGROUND: Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. METHODS: VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. RESULTS: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15µmol/L). At 6 months, one patient (metformin) had MMA >0.4µmol/L and 3 (2 metformin, 1 placebo) had HC > 15µmol/L. CONCLUSIONS: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Everolimus for advanced pancreatic neuroendocrine tumors.

BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early-stage breast cancer: A prospective trial.

BACKGROUND: We previously reported that postmenopausal women with ER+ breast cancer (BC) receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 (inadequate estrogen suppression [IES]) had a 3.0-fold increased risk of a BC event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5) among those with IES on ANA1. METHODS: Postmenopausal women with ER+ BC planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8-10 weeks of ANA1. Those with IES were switched to 8-10 week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of planned treatment (adherent cohort). RESULTS: 132 (84.6%) of 156 eligible patients were ANA1-adherent. IES occurred in 40 (30.3%) adherent patients. 25 (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90%CI: 58.1-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients. CONCLUSIONS: Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative AI.

Efficacy of first-line checkpoint inhibitors in combination with chemotherapy in high-grade extrapulmonary metastatic neuroendocrine carcinomas.

Poorly differentiated extrapulmonary neuroendocrine carcinomas (EP NECs) are aggressive cancers characterized by a high Ki-67 index, rapid tumor growth and poor survival, and are subdivided into small and large cell carcinoma. For small cell carcinoma of the lung, a pulmonary NEC, the combination of cytotoxic chemotherapy (CTX) and a checkpoint inhibitor (CPI) is considered standard therapy and superior to CTX alone. EP NECs are typically treated with platinum-based regimens, some clinicians have adopted the addition of a CPI to CTX based on data from trials in patients with small cell carcinoma of the lung. In this retrospective study of EP NECs, we report 38 patients treated with standard first-line CTX and 19 patients treated with CTX plus CPI. We did not observe any additional benefit of adding CPI to CTX in this cohort.

A phase II study of bevacizumab and temsirolimus in advanced extra-pancreatic neuroendocrine tumors.

We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered i.v. on days 1, 8, 15, and 22 and bevacizumab 10 mg/kg i.v. on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluated for efficacy and adverse events. While median progression-free survival was 7.1 months, the median duration of treatment with temsirolimus was 3.9 months and that with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of the patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred in the study, of which two were due to treatment-related bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.

Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer.

Importance: The American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown. Objective: To investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality. Design, Setting, and Participants: The Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor-negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023. Exposure: An aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle. Main Outcomes and Measures: Disease recurrence and all-cause mortality. Results: A total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59). Conclusions and Relevance: In this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial.

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

Breast medical oncologists' use of standard prognostic factors to predict a 21-gene recurrence score.

BACKGROUND: Half of all breast cancers are early stage, lymph node negative, and hormone receptor positive. A 21-gene (Oncotype DX®; Genomic Health, Inc., Redwood City, CA) recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit. We explored the ability of oncologists to predict the RS using standard prognostic criteria. METHODS: Standard demographic and tumor prognostic criteria were obtained from patients with an available RS. Two academic pathologists provided tumor grade, histologic type, and hormone receptor status. Six academic oncologists predicted the RS category (low, intermediate, or high) and provided a recommendation for therapy. The oncologists were then given the actual RS and provided recommendations for therapy. Analysis for agreement was performed. RESULTS: Thirty-one cases, including nine additional cases with variant pathology reads, were presented. There was substantial agreement in oncologists' ability to discriminate between true low or true intermediate and true high (κ = 0.75; p < .0001). Predictions between low and intermediate were not consistent. The most common discrepancies were predictions of a low RS risk when cases were true intermediate and predictions of an intermediate RS risk when cases were true low. The actual RS resulted in a change in the treatment recommendations in 19% of cases. Of the 186 scenarios and six oncologists in aggregate, five fewer chemotherapy recommendations resulted with the actual RS. CONCLUSIONS: Oncologists are able to differentiate between a low or intermediate RS and a high RS using standard prognostic criteria. However, provision of the actual RS changed the treatment recommendations in nearly 20% of cases, suggesting that the RS may reduce chemotherapy use. This effect was observed in particular in intermediate-risk cases. Prospective clinical trials are necessary to determine whether decisions based on the RS change outcomes.

Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents.

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened. We review the rationale for a modified approach to evaluation and outline the key steps that will optimize development of this agent in breast cancer, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.