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This article will review and summarize the current data regarding the influence of the major cytochrome P450 2D6 (CYP2D6) genotypes and CYP2D6 inhibitors on tamoxifen metabolism and clinical efficacy. We will discuss the clinical relevance and limitations of this data and how to best incorporate our current understanding of CYP2D6 genotyping into our clinical practice and discussions with patients.

CYP2D6 Testing in Breast Cancer: Ready for Prime Time?

Although the 70-Gene MammaPrint (MP) assay was not confirmed to be predictive of distant recurrence (DR) in patients with hormone receptor (HR)–positive, early-stage breast cancer, the assay predicted responses to extended letrozole (Femara) therapy (ELT) and identified subsets of patients with low-risk disease who experienced improved outcomes with ELT. These findings from the phase 3 NSABP B-42 study (NCT00382070) were published in the 

Data showed no statistically significant difference in ELT on DR between tumors classified as MP high risk (MP-HR) or low risk (MP-LR; 

 = .38). A statistically significant 10-year benefit of 3.7% was found for DR in MP-LR tumors, (HR, 0.43; 95% CI, 0.25-0.74, 

.002) but a nonsignificant 2.4% benefit was observed for DR with MP-HR tumors (HR, 0.65; 95% CI, 0.34-1.24; 

Compared with the overall population of the B-42 trial (n = 3903), a significantly improved prognosis for DR was noted among those in the translational MP cohort (n = 1866; 

.036). The study authors noted that the relatively low incidence of DR events—especially among tumors classified as ultralow-risk (MP-UL)—limited the study's power to assess this end point and detect significant differences in outcomes following ELT across subgroups.

There was a significant 10-year ELT benefit for disease-free survival (DFS) and breast cancer-free interval (BCFI) for MP-LR tumors not observed in those with MP-HR disease; the interaction between MP and ELT benefit reached statistical significance for these end points (DFS: interaction 

At 10 years, ELT benefit for DR was not statically significant for MP-UL tumors (HR, 0.53; 95% CI, 0.13-2.15; 

 = .37), although a significant effect occurred in low-non-ultralow risk (MP-LNUL) tumors (HR, 0.42; 95% CI, 0.24-0.77; 

 = .003). This difference was not statistically significant (interaction 

 = .89). At 10 years, the DR rate was 4.0%, the DFS rate was 9.5%, and the BCFI rate was 7.9% among those with MP-LNUL tumors. These benefits in the MP-LNUL subgroup were significant and more pronounced compared with those for patients with MP-UL tumors, where the respective 10-year rates were 3%, 1.8%, and 4.1%.

“Overall, these findings may expand the clinical utility of MP beyond prognostic indication because they provide the first evidence suggesting that MP is predictive of [extended endocrine therapy] benefit,” wrote Priya Rastogi, MD, vice-chair for medical affairs at the National Surgical Breast and Bowel Project and medical oncologist at the Magee-Womens Hospital of the University of Pittsburgh Medical Center, with study coinvestigators in the publication.

 “Future analyses incorporating clinicopathologic characteristics could also further optimize patient selection.”

Included in the prospective-retrospective correlative study were eligible patients with clinical follow-up and available untreated primary tumor tissue. Developers in Irvine, California received tumor blocks, and MP test scores were generated and blinded to clinical outcome. These test results were included in the final clinical data set.

Of patients randomly assigned to letrozole or placebo in the B-42 trial (n = 3966), blocks were available for 2338 patients, with a final translational MP cohort consisting of 1866.

The primary end point of the correlative study assessing the predictive abilities of MP was DR. Secondary end points in this analysis included DFS and BCFI. In the original NSABP-B42 trial, the primary end point was DFS.

The median follow-up time for patients included in the MP cohort was 10.4 years. In total, 706 (37.8%) and 1160 (62.2%) patients were MP-HR or MP-LR, with those in the MP-LR group further disaggregated into MP-UL (n = 252, 13.5%) and low-non-ultralow risk (MP-LNUL, n = 908, 48.7%) subtypes.

There were 102 DR and 457 DFS events observed in the translational cohort. A statistically significant ELT benefit for DFS was observed in the MP-LR group (HR, 0.67; 95% CI, 0.52-0.85; 

< .001) but not in the MP-HR group (HR, 1.10; 95% CI, 0.82-1.47; 

 = .55). Furthermore, a 7.8% improvement was observed in patients undergoing ELT for MP-LR tumors vs placebo, contrasting with a –1.6% difference reported in patients undergoing ELT for MP-HR tumors compared with placebo.

In BCFI, the assumption of hazards proportionality was not satisfied between treatment groups for the MP-HR subgroup; a change point of 5.2 years identified a distinguishable statistically significant difference in ELT effect between MP-HR (HR, 2.77; 95% CI, 1.28-5.99; 

= .01) and MP-LR (HR, 0.37; 95% CI, 0.21-0.66; 

< .001) subgroups. Prior to 5.2 years, ELT benefit was similar between MP-HR and MP-LR subgroups.

Rastogi P, Bandos H, Lucas PC, et al. Utility of the 70-Gene MammaPrint assay for prediction of benefit from extended letrozole therapy in the NRG Oncology/NSABP B-42 trial. 

 Published online July 24, 2024. doi:10.1200/JCO.23.01995

Letrozole in treating postmenopausal women who have received hormone therapy for hormone receptor-positive breast cancer. ClinicalTrials.gov. Accessed August 14, 2024. https://tinyurl.com/2dhreevh

NSABP B-42 trial results show that the assay was predictive of extended letrozole therapy response, identifying a patient subset with improved outcomes.

Gene Assay May Predict Extended Letrozole Benefits in Breast Cancer Subsets

An overall survival benefit was observed when patients with resectable esophageal cancer were given perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) vs neoadjuvant chemoradiation (CROSS), according to results from the phase 3 ESOPEC trial (NCT02509286) presented during the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

At a median follow-up of 55 months, patients in the intention-to-treat population who received the FLOT protocol (n = 221) achieved a median OS of 66 months (95% CI, 36-not evaluable [NE]) compared with 37 months (95% CI, 28-43) among those who were treated with the CROSS protocol (n = 217; HR, 0.70; 95% CI, 0.53-0.92; 

 = .012). The 3-year OS rates were 57.4% vs 50.7%, respectively, and the 5-year OS rates were 50.6% vs 38.7%, respectively.

Additionally, the median progression-free survival (PFS) was 38 months (95% CI, 21-NE) in the FLOT arm compared with 16 months (95% CI, 12-22) in the CROSS arm (HR, 0.66; 95% CI, 0.51-0.85; 

 = .001). The 3-year PFS rates were 51.6% vs 35.0%, respectively, and the 5-year PFS rates were 44.4% vs 30.9%, respectively.

“Many patients in the US and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term,” Jens Hoeppner, FAChirg, FACS, MD, the director of the Department of Surgery at University Medical Center, University of Bielefeld, in Detmold, Germany, stated in a press release.

ESOPEC was a prospective multicenter study that enrolled patients with esophageal adenocarcinoma across 25 sites in Germany between February 2016 and April 2020. Eligible patients needed to be at least 18 years old, have received no prior abdominal or thoracic radiotherapy, have an ECOG performance status of 2 or less, and have adequate organ function. Patients were also required to have pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease. The presence of squamous or other non-adenocarcinoma histology, gastric cancer, clinical stage cT1cN0 and cT4b disease, or metastatic disease excluded patients from enrollment.

Patients were randomly assigned 1:1 to receive either the FLOT or CROSS protocol. Those in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles prior to surgery and 4 adjuvant cycles after surgery. In the CROSS arm, patients received neoadjuvant radiation therapy and concurrent chemotherapy with carboplatin and paclitaxel for 5 cycles in 5 weeks prior to surgery. Following neoadjuvant treatment, patients in both arms waited 4 to 6 weeks before proceeding to surgery.

The primary end point was OS. Secondary end points included PFS, recurrence-free survival, postoperative pathological stage, postoperative complications, and postsurgical quality of life.

At baseline, the mean age of patients in the FLOT and CROSS arms was 63.1 years (standard deviation [SD], 8.6) vs 62.6 years (SD, 9.8), respectively. Most patients in both arms were male (89.1% vs 89.4%), had clinical T-stage cT3-4 disease (79.1% vs 81.9%), and had clinical N-stage cN+ disease (77.8% vs 81.6%). Overall, 191 patients in the FLOT arm underwent surgery compared with 180 patients in the CROSS arm.

Additional findings from ESOPEC showed that the pathological complete remission rates among patients who underwent surgery in the FLOT arm was 16.8% compared with 10.0% in the CROSS arm. In both arms, complete regression (18.3% vs 13.3%) or near complete regression (25.1% vs 39.4%) was observed. Most patients across both arms underwent an R0 resection (94.2% vs 95.0%).

Patients in the predefined protocol population in the FLOT (n = 207) and CROSS (n = 196) arms achieved a median OS of 66 months (95% CI, 38-NE) vs 39 months (95% CI, 29-45), respectively (HR, 0.72; 95% CI, 0.54-0.96; 

 = .023). The 3-year OS rates were 58.1% vs 52.6%, respectively, and the 5-year OS rates were 51.8% vs 40.5%, respectively.

Results from an exploratory subgroup analysis demonstrated that the OS benefit in favor of FLOT vs CROSS was observed in all subgroups examined. The most pronounced benefit was reported in patients aged less than 60 years (HR, 0.57; 95% CI, 0.34-0.95) and those with clinical T-stage T3-4 disease (HR, 0.68; 95% CI, 0.50-0.92).

Most patients in both the FLOT and CROSS arms started neoadjuvant treatment; these patients comprised the predefined protocol population. A majority of patients in both arms completed neoadjuvant treatment (87.3% vs 67.7%) and received neoadjuvant treatment plus surgery (86.0% vs 82.9%). In the FLOT arm, 63.3% of patients received adjuvant treatment and 52.5% completed adjuvant treatment.

In the 90 days post-surgery, 3.2% of patients in the FLOT arm died compared with 5.6% in the CROSS arm. The 30-day postoperative mortality rates were 1.0% vs 1.7%, respectively At the data cutoff, 97 and 121 patients died in these respective arms.

“Perioperative chemotherapy with FLOT plus surgery improves OS compared with neoadjuvant chemoradiation with CROSS plus surgery in patients with locally advanced, resectable esophageal adenocarcinoma. ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival in resectable esophageal adenocarcinoma,” Hoeppner concluded in an oral presentation.

Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial).

. 2024;42(suppl 17):LBA1. doi:10.1200/JCO.2024.42.17_suppl.LBA1

Chemotherapy before and after surgery may be new standard treatment for some patients with esophageal cancer. News Release. ASCO. June 2, 2024. Accessed June 2, 2024. https://society.asco.org/about-asco/press-center/news-releases/chemotherapy-and-after-surgery-may-be-new-standard-treatment

Perioperative chemotherapy compared to neoadjuvant chemoradiation in patients with adenocarcinoma of the esophagus (ESOPEC). ClinicalTrials.gov. Updated May 8, 2024. Accessed June 1, 2024. https://clinicaltrials.gov/study/NCT02509286

study was published on June 2, 2024, from the press briefing, and was updated on June 4, 2024, with additional information/data from the oral session.

The combination of perioperative chemotherapy plus FLOT improved overall survival vs neoadjuvant chemoradiation in patients with resectable esophageal cancer. 


Conference

OS Prolonged With Perioperative Chemo Vs Neoadjuvant CRT in Esophageal Cancer 

The FDA has accepted a biologics license application (BLA) for a subcutaneous formulation including nivolumab (Opdivo) and hyaluronidase (rHuPH20) for adult patients with solid tumors for which standard intravenous nivolumab has already received approval, according to a press release from the developers, Bristol Myers Squibb.

If approved, patients would be eligible to receive subcutaneous nivolumab as monotherapy, monotherapy maintenance after receiving prior nivolumab plus ipilimumab (Yervoy), or as part of a combination regimen including chemotherapy or cabozantinib (Cabometyx). The regulatory agency has set a Prescription Drug User Fee Act date of February 28, 2025, for its decision on approving the subcutaneous formulation of the agent.

(Editor's Note: As of May 21, 2024, the FDA updated the Prescription Drug User Fee Act date for subcutaneous nivolumab to December 29, 2024.)

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” Gina Fusaro, PhD, vice president and global program lead at Bristol Myers Squibb, said in the press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as [intravenous nivolumab] but with the improved convenience of an injection administered in 3-to-5 minutes rather than a 30-to-60-minute infusion.”

Supporting findings for the BLA came from the 

phase 3 CheckMate-67T trial (NCT04810078),

 in which investigators compared treatment with intravenous vs subcutaneous nivolumab in previously treated patients with advanced or metastatic clear cell renal cell carcinoma (RCC). Updated findings from the CheckMate-67T trial were presented at the 

In the CheckMate-67T trial, 495 patients were randomly assigned to receive either subcutaneous (n = 248) or intravenous (n = 247) nivolumab. ORR was a key secondary end point of the trial.

Regarding the coprimary end point of time-averaged nivolumab serum concentration over 28 days (Cavgd28), treatment with subcutaneous nivolumab demonstrated noninferiority compared with the intravenous formulation with a geometric mean ratio of 2.098 (90% CI, 2.001-2.200).

 Additionally, the subcutaneous formulation exhibited noninferiority with respect to the coprimary end point of trough serum concentration at steady state (Cminss) with a geometric mean ratio of 1.774 (90% CI, 1.633-1.927).

The objective response rate (ORR) was 24.2% with subcutaneous nivolumab vs 18.2% with the intravenous formulation (relative risk, 1.33; 95% CI, 0.94-1.87). Additionally, the median progression-free survival according to blinded independent central review was 7.23 months vs 5.65 months, respectively.

Grade 3/4 adverse effects (AEs) occurred in 35.2% of patients in the subcutaneous arm vs 40.8% of those in the intravenous arm. Additionally, 9.7% and 14.7% of patients in each respective arm had treatment-related AEs, 21.1% and 22.9% had serious AEs, and 6.5% and 6.5% experienced treatment-related serious AEs.

Investigators concluded that the safety profile of subcutaneous nivolumab was comparable with prior reports of the intravenous formulation.

“The data from CheckMate-67T with the subcutaneous formulation of nivolumab co-formulated with recombinant human hyaluronidase represent a groundbreaking advancement in oncology research for physicians and our patients,” Saby George, MD, FACP, a professor of Oncology and Medicine and the director of Network Clinical Trials in the Department of Medicine at Roswell Park Comprehensive Cancer Center said in a press release about these data.

“Having the option to administer immunotherapy subcutaneously could undoubtedly reduce the treatment burden that patients diagnosed with cancer currently [have], as well as help maximize efficiencies within healthcare systems. As it stands, intravenous immunotherapy infusion can take precious time, which we know is an important commodity for patients and the doctors who treat them. That’s why these results indicating noninferiority with subcutaneous nivolumab have the potential to be practice-changing and to improve patients’ treatment experience with one injection that can be given in under five minutes and, in some cases, outside of the infusion center,” George concluded.

U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. https://bit.ly/3JL8yY1

Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 21, 2024. Accessed May 21, 2024. https://tinyurl.com/3emkwdk2

Subcutaneous nivolumab (nivolumab and hyaluronidase) shows noninferiority compared to intravenous Opdivo (nivolumab) in advanced or metastatic clear cell renal cell carcinoma in CheckMate -67T trial. News release. Bristol Myers Squibb. January 27, 2024. Accessed May 6, 2024. https://bit.ly/4dvCMvQ

Data from the CheckMate-67T trial support the biologics license application for subcutaneous nivolumab in multiple solid tumors.

FDA Accepts BLA for Subcutaneous Nivolumab in Solid Tumor Indications

A 22-year-old Caucasian woman presented with a four month history of pain, tenderness and swelling in her right breast. Initial treatments with antibiotics and steroids were unhelpful. She had continued to have diffuse swelling and tenderness in her right breast and also noted bruising on the overlying skin. An ultrasound of the right breast showed a large, diffuse, irregular, echogenic lesion, suggesting inflammation or tumor. A mammogram confirmed diffuse mass-like density corresponding to the echogenic mass seen on the ultrasound. A bilateral breast magnetic resonance imaging (MRI) reported diffuse abnormal signal and enhancement throughout the entire right breast (

. A right breast needle biopsy was performed (

C. Metaplastic carcinoma with angiosarcoma differentiation 

A 22-year-old Caucasian woman presents with a four month history of pain, tenderness and swelling in her right breast. What's your diagnosis?

Image IQ

A 22-Year-Old Woman With Pain, Tenderness and Swelling in the Breast

A 28-year-old woman with a history of nephrolithiasis has an abdomen CT scan to investigate an abnormality in the liver detected on a prior non-contrast CT performed in the emergency department. She has no other medical issues. Axial images from a contrast-enhanced CT scan are shown below (Figure 1 arterial and Figure 2 delayed phases).

A 28-year-old woman with a history of nephrolithiasis has an abdomen CT scan to investigate an abnormality in the liver. What is your diagnosis?

Poll 

Liver Abnormality in 28-Year-Old Patient

We present a 65-year-old man with multiple myeloma who developed a rare complication of pleural effusion. Initial laboratory results showed elevated creatinine, calcium, and protein electrophoresis with an M spike. A bone marrow biopsy confirmed 80% plasma cells. Despite the rarity of pleural effusion in patients with multiple myeloma, our patient demonstrated significant improvement with targeted therapy and palliative care. This case highlights the importance of early recognition and management of pleural effusion in patients with multiple myeloma and underscores the need for further research into optimal management strategies and underlying mechanisms.

Multiple myeloma is a cancer of plasma cells that produces monoclonal proteins (M protein). The term 

This refers to the tumors that develop in the bone marrow due to the malignant plasma cell proliferation, leading to bone destruction, anemia, and immune dysfunction.

Multiple myeloma is the second most common hematologic malignancy, accounting for approximately 1% of all cancers and 10% of hematologic malignancies.

This case highlights the importance of early recognition and management of pleural effusion in patients with multiple myeloma and underscores the need for further research into optimal management strategies and underlying mechanisms.

Nicole M. Kuderer, MD

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