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Burnout in medicine is not new—the syndrome was described in 1974 by psychologist Herbert J. Freudenberger as a condition that occurs when occupation-related stress combined with additional life pressures exceed an individual’s ability to cope and thrive, resulting in physical and mental distress.

 Trauma and stress related to the COVID-19 pandemic, coupled with subsequent widespread labor shortages, have turned what was an endemic issue in medicine to a pandemic of burnout in health care.

Longitudinal work evaluating the prevalence of burnout among physicians in the United States between 2011 and 2021 demonstrated that 62.8% of physicians surveyed in 2021 reported at least 1 burnout-related symptom compared with 38.2% (

 Given that burnout has been linked to higher rates of depression, substance use disorders, suicide, medical errors, and reduction in work hours, these findings have profound consequences not only for physicians and other members of the health care team, but for the practice of medicine more broadly.

Recent reports have focused on the pandemic’s impact on physician burnout in fields including emergency medicine, critical care, and hospital medicine.

 Oncologists and other members of the oncology care team face challenges inherent to their work that place them at high risk of burnout, such as caring for a high proportion of terminally ill patients, counseling families, and prescribing and managing potentially toxic therapies.

Shanafelt et al conducted a survey assessing burnout and related predictors in a cohort of 1998 US-based oncologists identified through membership files of the American Society of Clinical Oncology (ASCO) in 2013.

 Burnout was assessed through the Maslach Burnout Inventory, a standardized measure that assesses the 3 primary domains of burnout (emotional exhaustion, depersonalization, and a feeling of low personal accomplishment).

Among a final sample size of 1490 respondents, 44.7% reported at least 1 symptom of burnout. Moreover, 38.3% reported emotional exhaustion, 24.9% depersonalization, and 13.2% a sense of low personal achievement. A multivariate analysis revealed that younger age (

 < .001), higher number of hours providing direct patient care (

 < .001), higher number of hours performing work-related tasks at home (

 = .039) and focus on an individual type of cancer (

 = .027) were factors significantly associated with higher risk of burnout.

The survey also identified significant differences in the factors associated with burnout in the private practice vs academic settings. In private practice, having children was associated with lower risk of burnout (

 = .036), whereas spending more time engaged in administrative work was associated with higher risk of burnout (

 = .003). In academic practice, being female (

 = .042), having shorter appointment lengths for return patients (

 = .049), and having more weekends on call (

 = .002) were associated with higher risk of burnout.

Studies have also evaluated the prevalence and drivers of burnout in nonphysician members of the oncology care team. A 2019 survey assessed burnout and its relationship to workplace factors in members of the Association of Physician Assistants in Oncology.

Of 342 survey respondents 48.7% met the definition of burnout, with 43.6% having a high score on the emotional exhaustion scale and 22.2% on the depersonalization scale. Although patient volume was not associated with burnout, physician assistants who perceived a higher workload were at increased risk of burnout (

 = .001). Physician assistants who spent more time practicing in a manner consistent with their education and experience were at lower risk of burnout; those who spent at least 75% of their time working at top of license had a burnout rate of 43.4% compared with 56.7% for those who spent less than 75% of their time working at this level. Finally, mismatch between individual and workplace values (

 = .008) were also associated with increased risk of burnout.

A similar survey collected information about burnout among oncology pharmacists (n = 614) in 2020.

 Most respondents (61.8%) met the definition of burnout, with 57.9% having high scores on the emotional exhaustion scale and 31.3% scoring high on the depersonalization scale. Pharmacists who met the definition of burnout worked more hours (48.6 ± 9.6 h/wk vs 44.5 ± 9.6 h/wk; 

 < .001) and spent more time on administrative (7.5 hours/week vs 4.3 h/wk; 

 < .001) compared with those who did not meet the definition.

These surveys suggest that burnout is prevalent across the oncology care team, with high rates of emotional exhaustion. Long work hours were related to higher rates of burnout across professions. However, other predictors of burnout differed depending on job role and practice setting, suggesting that strategies to mitigate burnout must be individualized to be impactful.

Mitigating Burnout and Supporting Professional Well-Being

To address the growing threat that burnout poses to the health care workforce, many organizations, including the American Medical Association (AMA) and the National Academy of Medicine, have supported work to explore the drivers of burnout and develop initiatives to mitigate it and reinforce professional well-being in health care workers.

The AMA commissioned a landmark report in 2013 that highlighted the importance of delivering high-quality care to increase professional satisfaction, pros and cons of electronic health records, value of income stability and fairness, and cumulative burden of regulations.

This work has led to the development of online resources, such as the STEPS Forward toolkits, aimed at mitigating burnout and supporting clinician well-being.

In 2019, the National Academy of Medicine published a consensus report titled, “Taking Action Against Clinician Burnout: A Systems Approach to Professional Well-Being.” The report categorized the causes of burnout and recommended a multi-pronged action plan that included the creation of positive work and learning environments, reduction of administrative burden, optimization of information technologies, provision of support for clinicians and trainees, and investment in research on clinician well-being.

The ASCO has focused on developing initiatives to address burnout in the oncology work force. In 2020, ASCO created a Clinician WellBeing Task Force as a collaborative effort between ASCO committees, with the goal of coordinating efforts to address burnout in oncology clinicians.

 The group has a transdisciplinary membership, including ASCO volunteers with expertise in oncology, psychology/psychiatry, nursing/advanced practice, burnout/well-being, professional/organizational development, ethics, and cancer administration.

The ASCO task force subsequently developed a roadmap outlining the mission and the 5-year goals of the ASCO Well-Being initiative. Key objectives of the task force include incorporating clinician well-being across ASCO activities, broadening resources to support well-being, and promoting research to identify clinician practice needs. It is also committed to collecting longitudinal data regarding the prevalence and predictors of burnout in oncology clinicians. The initiative planned to conduct an additional survey assessing the prevalence and predictors of burnout in ASCO physician members in January of 2023 to help guide further recommendations and initiatives (

Burnout is a growing problem in oncology and in medicine more broadly. Longer work hours drive high rates of burnout across professional roles, but other drivers of burnout are more specific to job roles and work environment. Developing meaningful initiatives to mitigate the factors contributing to burnout will require societal level change and commitments at the level of individual institutions. Coordinated efforts by organizations like the AMA, National Academy of Medicine, and ASCO will play a critical role in driving the changes needed to support both clinicians and high-quality care for patients.

Jennifer A. Ligibel, MD, is director of the Leonard P. Zakim Center for Integrative Therapies and Healthy Living, director of the Center for Faculty Well-Being, and a senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts. 

Hlubocky FJ, Shanafelt TD, Back AL, et al. Creating a blueprint of well-being in oncology: an approach for addressing burnout from ASCO’s Clinician Well-Being Taskforce. 

. 2021;41:e339-e353. doi:10.1200/EDBK_320873

Shanafelt TD, West CP, Dyrbye LN, et al. Changes in burnout and satisfaction with work-life integration in physicians during the first 2 years of the COVID-19 pandemic. 

. 2022;97(12):2248-2258. doi:10.1016/j.mayocp.2022.09.002

Shanafelt TD, Sloan JA, Habermann TM. The well-being of physicians. 

. 2003;114(6):513-519. doi:10.1016/s00029343(03)00117-7

Shanafelt TD, Balch CM, Dyrbye L, et al. Special report: suicidal ideation among American surgeons. 

. 2011;146(1):54-62. doi:10.1001/archsurg.2010.292

Oreskovich MR, Kaups KL, Balch CM, et al. Prevalence of alcohol use disorders among American surgeons. 

. 2012;147(2):168-174. doi:10.1001/archsurg.2011.1481

Shanafelt TD, Balch CM, Bechamps G, et al. Burnout and medical errors among American surgeons. 

. 2010;251(6):995-1000. doi:10.1097/SLA.0b013e3181bfdab3

Shanafelt TD, Gradishar WJ, Kosty M, et al. Burnout and career satisfaction among US oncologists. 

. 2014;32(7):678-686. doi:10.1200/JCO.2013.51.8480

Mazur LM, Adapa K, Meltzer-Brody S, Karwowski W. Towards better understanding of workplace factors contributing to hospitalist burden and burnout prior to COVID-19 pandemic. 

. 2023;106:103884. doi:10.1016/j.apergo.2022.103884

Golbach AP, Mccullough KB, Soefje SA, Mara KC, Shanafelt TD, Merten JA. Evaluation of burnout in a national sample of hematology-oncology pharmacists. 

. 2022;18(8):e1278-e1288. doi:10.1200/OP.21.00471

Tetzlaff ED, Hylton HM, Ruth KJ, Hasse Z, Hall MJ. Association of organizational context, collaborative practice models, and burnout among physician assistants in oncology. 

. 2022;18(8):e1306-e1319. doi:10.1200/OP.21.00627

Friedberg MW, Chen PG, Van Busum KR, et al. Factors affecting physician professional satisfaction and their implications for patient care, health systems, and health policy. 

National Academies of Sciences, Engineering, and Medicine; National Academy of Medicine; Committee on Systems Approaches to Improve Patient Care by Supporting Clinician Well-Being. 

Taking Action Against Clinician Burnout: A Systems Approach to Professional Well-Being

. Washington (DC): National Academies Press (US); October 23, 2019.

ASCO Oncology Clinician Well-Being Task Force roadmap. American Society of Clinical Oncology. Accessed January 5, 2023. bit.ly/3X4kZ6l

Articles

Trauma and stress related to the COVID-19 pandemic, coupled with subsequent widespread labor shortages, have turned burnout, which was an endemic issue in medicine, to a pandemic in health care.

Slow Burn to Wildfire: How Do We Douse the Flames of Burnout in Oncology?

The response rates to agents available in the third or later lines of therapy for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have improved significantly with the advent of chimeric antigen receptor (CAR) T-cell therapies such as lisocabtagene maraleucel (Breyanzi). However, alternative options are needed for patients who cannot access the therapy or who experience disease progression after receiving it.

Advances in the development of bispecific antibodies have demonstrated response rates close to or surpassing those of other agents in development, offering investigators an avenue to pursue phase 3 studies such as EPCORE DLBCL-1 (NCT04628494) to challenge standard of care with the CD3 × CD20 agent, epcoritamab.

Patients with high-risk DLBCL have a 5-year overall survival (OS) rate of 49% to 61% per varying criteria.

 “Relapsed Raúl Córdoba Mascuñano, MD, PhD or refractory DLBCL remains very difficult to treat. We can cure up to two-thirds of patients [with DLBCL], but one-third of patients cannot be cured when given frontline therapy with regimens such as R-CHOP [rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone],” Raúl Córdoba Mascuñano, MD, PhD, said in an interview with 

. Up to 15% of patients treated who receive R-CHOP will have either an incomplete response or a relapse within 6 months of treatment. Nearly one-quarter of patients will relapse within in 2 years of R-CHOP.

“It’s not easy to cure these patients who have relapsed disease,” said Córdoba Mascuñano, who is coordinator of the Lymphoma Unit at Jiménez Díaz Foundation University Hospital in Madrid, Span. “However, we have a second attempt to cure these patients when we offer second-line chemotherapy plus autologous stem cell transplant [ASCT].” Although ASCT provides the best option for patients to achieve cure, most patients are either ineligible for transplant or relapse after the procedure.

Patients may not be candidates for ASCT for several reasons, including fitness, which takes into account age, comorbidities, and response to prior therapies.

 In those eligible for transplant, the cure rate is approximately 25% to 30%, with only half of patients responding to salvage therapy prior to transplant.

Palliative treatment options for patients who do not respond to therapy include bendamustine (Bendeka) plus rituximab or rituximab plus gemcitabine and oxaliplatin (R-GemOx). Additional treatments such as antibody-drug conjugates have response rates of up to 50% in phase 1 or phase 2 studies, whereas monoclonal antibodies have response rates of up to 60% in phase 2 studies. CAR T-cell therapies have the highest documented response (82%); however, the availability and cost of such therapies remain a barrier for patients.

Several bispecific antibodies are in development for patients with relapsed or refractory large B-cell lymphoma (LBCL) and are being evaluated in phase 1 or phase 2 studies. Blinatumomab, a bispecific T-cell engager, is designed to target CD19 and CD3 and has demonstrated a response rate of 43% among 19 evaluable patients.

 Like epcoritamab, mosunetuzumab, glofitamab, and odronextamab are engineered to target CD3 on T cells and CD20 on B cells, with response rates ranging between 32% and 42%.

Data from a dose-expansion cohort of the EPCORE NHL-1 study (NCT03625037) showed that among 157 individuals who received the CD3 × CD20 bispecific antibody, the overall response rate (ORR) was 63.1% (95% CI, 55.0%-70.6%) and the complete response (CR) rate, 38.9% (95% CI, 31.2%-46.9%). Responses lasted for a median of 1 year; the median duration of response (DOR) among those who achieved a CR was not reached. At 6 and 9 months, an estimated 88.7% of complete responders were reported as still deriving benefit from single-agent epcoritamab.

The median time to any response and to CR was 1.4 months (range, 1.0-8.4) and 2.7 months (range, 1.2-11.1), respectively. Median progression-free survival (PFS), a secondary end point of the study, was 4.4 months (95% CI, 3.0-7.9) with a PFS rate of 43.9% (95% CI, 35.7%-51.7%) at 6 months. At the time of the analysis, median overall survival (OS) was not reached (95% CI, 11.3-NR).

Minimal residual disease (MRD), a marker under exploration with greater focus in LBCL, was an exploratory objective in the study and was evaluable in 107 patients. MRD-negativity was observed in 45.8% (95% CI, 36.1%-55.7%) of patients and the 6-month MRD-negativity rate was estimated at 78.7%. In an analysis of outcomes by MRD-negativity, investigators reported that PFS was longer than the general population in those with MRD-negative status.

Most patients enrolled in the study had DLBCL (88.5%). Other CD20-positive mature B-cell neoplasms included primary mediastinal LBCL (n = 4; 2.5%), follicular lymphoma (n = 5; 3.2%), and high-grade B-cell lymphoma not otherwise specified (n = 9; 5.7%). Patients received a median of 5 cycles of treatment (range, 1-20), equating to 15 doses. At data cutoff, 32.5% of patients remained on treatment.

Ninety-six patients had primary refractory disease at baseline. The ORR among this subgroup was 55.2%, with a CR rate of 30.2%. Prior to enrollment, 61 patients received CAR T-cell therapy (38.9%). More than half of patients had a response (54.1%), and 34.4% of responders had a CR. The median DOR was 9.7 months (95% CI, 5.4-NR). For patients who did not receive prior CAR T-cell therapy the ORR was 68.8% with a CR rate of 41.7%, and the median DOR was NR.

A safety analysis showed that grade 3 or higher treatment emergent adverse effects (TEAEs) were reported among 61.6% of patients, resulting in 11 patients discontinuing treatment. The most common grade 3 or higher TEAEs included neutropenia (14.6%), anemia (10.2%), thrombocytopenia (5.7%), and cytokine release syndrome (CRS; 2.5%). Any-grade CRS occurred in 49.7% of patients on study, and the median time to resolution was 2 days. AEs of interest included immune effector cell–associated neurotoxicity syndrome (ICANS), which occurred in 6.4% of patients, with 1 patient experiencing a grade 3 or higher event. Clinical tumor lysis syndrome was document in 2 patients and both events were grade 3 or higher in severity.

Twelve patients discontinued treatment due to TEAEs, with CRS and ICANS attributed to 1 patient each. Nine patients died on study and investigators reported that no grade 5 events were attributed to epcoritamab.

Based on data from this study the FDA accepted a biologics license application for epcoritamab for adult patients with relapsed or refractory LBCL who have received 2 or more prior lines of therapy.

Additional studies have been undertaken with epcoritamab for patients with DLBCL ineligible for ASCT, specifically in combination with GemOx in arm 5 of the phase 1/2 EPCORE NHL-2 trial (NCT04663347).

At a data cutoff of December 2021, 27 patients with a median age of 71 years (range, 47-87) received epcoritamab plus GemOx. The median number of prior therapies for this population was 2 (range, 1-13) and more than half of patients (59%) remained on treatment at the time of analysis.

Two patients died within 60 days of the first dose and were not evaluable for response. ORR for this cohort of patients was 92% with a complete metabolic response rate of 60% and a partial metabolic response rate of 32%. The longest duration of response was 6.9 months.

In terms of safety, 4 patients died on treatment and investigators noted that no deaths were attributed to epcoritamab. The most common TEAEs were CRS (70%), thrombocytopenia (70%), and neutropenia (56%). Most cases of CRS occurred in cycle 1, were grade 1 or grade 2 in severity, and had a median time to resolution of 2 days. No patients discontinued treatment due to CRS. Of note, 3 patients had received prior CAR T-cell therapy and all remained on treatment in response.

EPCORE DLBCL-1 will further explore singleagent epcoritamab against standard-of-care chemotherapy of investigator’s choice among patients with relapsed or refractory DLBCL who were either ineligible for or did not respond to treatment with ASCT (

 The primary efficacy measure is OS, with secondary outcomes of PFS, ORR, CR, DOR, time to response, and rate and duration of MRD negativity, which will be determined as having at least 1 negative MRD sample at any time prior to the start of subsequent antilymphoma therapy.

CD20-positive disease must be identified among those with DLBCL not otherwise specified, including de novo or follicular lymphoma that was histologically transformed, double- or triple-hit DLBCL, grade 3B follicular lymphoma, T-cell LBCL, or histiocyte-rich LBCL. Patients must have an ECOG performance status of 0 to 2 and acceptable liver and renal function as well as an anticipated life expectancy of more than 2 months on standard-of-care chemotherapy. Of note, patients with primary central nervous system tumors are not eligible for this trial. Prior treatment with a CD3 × CD20 bispecific antibody is not permitted.

Epcoritamab will be administered as a subcutaneous injection following required premedication, which include step-up dosing and corticosteroid prophylaxis during the first cycle to mitigate CRS. Investigator choice chemotherapy options include either bendamustine plus rituximab or R-GemOx.

Shen LH, Salles G. Diffuse large B-cell lymphoma. 

. 2021;384(9):842-858. doi:10.1056/NEJMra2027612 

Shah H, Stephens D, Seymour J, Maddocks K. Incorporating novel targeted and immunotherapeutic agents in the treatment of B-cell lymphomas. 

FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA. February 5, 2021. Accessed January 18, 2023. bit.ly/31ALyIj 

A phase 3 trial of epcoritamab vs investigator’s choice chemotherapy in R/R DLBCL (EPCORE DLBCL-1). ClinicalTrials.gov. Updated January 11, 2023. Accessed January 20, 2023. https:// clinicaltrials.gov/ct2/show/NCT04628494 

Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. 

. 2016;127(11):1410-1416. doi:10.1182/blood-2015-06-651380 

Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. 

. 2019;134(suppl 1):6. doi:10.1182/blood-2019-123742 

Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. 

. 2021;39(18):19591970. doi:10.1200/JCO.20.03175 

Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. 

. 2022;9(5):e327-e339. doi:10.1016/S2352-3026(22)00072-2 

Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell–engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. 

. Published online December 22, 2022. doi:10.1200/JCO.22.01725 

U.S. FDA accepts for priority review the biologics license application for epcoritamab (DuoBody-CD3xCD20) for the treatment of relapsed/refractory large B-cell lymphoma. News release. AbbVie. November 21, 2022. Accessed January 20, 2023. bit.ly/3D3EIuD 

Wahlin BE, Brody J, Phillips T, et al. Subcutaneous epcoritamab with GemOx induced high response rates in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant. 

. 2022;6:10991100. doi:10.1097/01.HS9.0000847716.29326.a8

Advances in the development of bispecific antibodies have demonstrated response rates close to or surpassing those of other agents in development, offering investigators an avenue to pursue phase 3 studies such as EPCORE DLBCL-1 to challenge standard of care with the CD3 × CD20 agent, epcoritamab in diffuse large B-cell lymphoma.

EPCORE Pushes CD3 × CD20 Bispecific Antibody Into Next Phase of Exploration in DLBCL

Specificity remains a top priority as investigators anticipate the trends that will dominate oncology practice in 2023. Innovation in molecular analysis, genomic testing, and screening have aided in the development of novel therapeutics; however, in the community setting, oncologists are facing barriers to fruits of the bench side labor. Therefore, in the coming year a renewed focus on dismantling the barriers and closing gaps in care will aid in the mission to drive down the rate of cancer mortality and incidence across disease states.

The 2023 cancer statistics report published by the American Cancer Society cited a 33% cancer death rate decline since 1991, with a 1.5% decline between 2019 and 2020. Declines in rate of mortality have been noted in tumor types such as leukemia, melanoma, and renal cancer even as the incidence of cancer in these areas has seen an increase.2 

Approximately 2 million new cancers are expected in 2023, with prostate, lung, and colorectal cancer (CRC) as the leading diagnoses in men (combined 48%), and breast, lung, and CRC accounting for 52% of diagnoses in women.2 Prostate (29%) and breast (31%) have the highest anticipated incidence rate among men and women, respectively.

Gains in survival have been on the rise with the 5-year survival rate for patients with a diagnosis made between 2012 and 2018 reaching 68% compared with 49% for patients who received a diagnosis in the 1970s. A component of these increases is better stratification of patients to therapies targeting driver mutations.

The National Opinion Research Center, or NORC, at the University of Chicago in Illinois cites that only 14% of cancers detected through a preventive screening test.3 Using a proprietary algorithm to detect the percent of cancers detected by screening (PCDS), the organization noted that among all cancers, 14.1% of breast, cervical, CRC, and lung cancer diagnoses are made through screening, with 11% of prostate cancers also being diagnosed this way. By cancer type, 61.3%, 51.5%, 45.4%, and 77%, of breast, cervical, CRC, and prostate cancers are detected by screening with mammography, Papanicolaou tests, recommended testing such as colonoscopies, and prostate-specific antigen (PSA) tests being the most notable, respectively.

In lung cancer, early detection is minimal in this area, with only 3% of diagnoses made through preventative screening.

 has shown that guidelines for cancer screening may not offer a clear identif ication of associated harms related to screening tests. Investigators of the report analyzed guideless from 33 sources including the National Comprehensive Cancer Network guidelines, to identify whether adequate information about screening is offered beyond that benefits of an assay outweigh the harm of a diagnosis. Some of the key harms identified in the report highlighted no standardization of interventions and a lack of available data on repeat assays, overdiagnosis, and possible exposure to unnecessary radiation.

Experts have concluded in published literature that cancers which are curable in early stages, such as anal, bladder, breast, CRC, renal, lung, melanoma, among others, would benefit from early detection. However, due to the variability of screening across cancer types a consensus on a one-size-identifies-most assay remains elusive and not widely recommended.

For now, advances in individual tumor types should undergo evidence-based review by expert panels for the purpose of a cost-benefit analysis. In CRC, for example, the findings from the recently reported at-home test for disease detection in the phase 3 CRC-PREVENT trial (NCT04739722), may provide opportunities to improve outcomes for a broader panel of patients.

 In this study, specifically, the investigators evaluated the efficacy of the RNA biomarker test among 8289 participants from diverse racial, ethnic, and socioeconomic backgrounds. In a comparison with results from a colonoscopy conducted within 120s of the at-home test, the test had a 94% sensitivity for CRC detection, a 45% sensitivity for advanced adenomas, and an 88% specificity for no f indings on a colonoscopy.

Prior to integration, guideline reviewers should be open about what harms and benefits being considered prior to the publication and should be as specific as possible. These justifications will not just better equip clinicians in practice but allow for patients and caregivers to weigh the value behind the recommendation prior to making a decision, especially if it calls for an invasive procedure.

Access to and the availability of these tools at the community level remains a hurdle for the future of this practice as well. For instance, in a report at the 64th American Society of Hematology Annual Meeting and Exposition, less than half (40%) of patients with heavily pretreated relapsed or refractory multiple myeloma designated to undergo chimeric antigen receptor (CAR) T-cell therapy received the treatment within 1 year. The study of patients able to access idecabtagene vicleucel (Abecma; ide-cel) at 2 institutions showed that 1.34% of patients received the therapy at 3 months, with 31.9% of patients dying before they were able to receive the CAR T therapy. Further, 12% of patients were removed from waiting and over one-quarter of patients (27%) were still waiting at 1 year.

Limited production was cited as the main cause of delays in the analysis; however, it is reflective of larger systemic issues. As uptake in academic and institutional settings increases, challenges facing the practitioner in the general setting may include administrative barriers, technological access, delays in reporting, and educational gaps.

In a closer look at hematologic malignancies, Joseph Mikhael, MD, noted that early access and detection are paramount issues for patients with multiple myeloma in ethnic and minority groups. “We can sadly talk all day about disparity, but [to] summarize the top 5 things that come to mind are: No. 1, the time to diagnosis, No. 2, time to therapy, No. 3, access to specialized centers, No. 4, the 4 T—access to triplets, transplants, trials, and CAR-T, and No. 5, physician bias,” said Mikhael, who is a professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute in Phoenix, Arizona. Mikhael is also the chief medical officer of the International Myeloma Foundation, which is actively trying to reduce the gap in time to diagnosis through awareness campaigns at the both the community and physician level. “[This is a] bi-modal approach, not just doing the deep engagement with both the medical and nonmedical communities, [but also] working with the National Medical Association and Black Nurses Association. We’re going deep into the primary care community to raise awareness [to address questions such as:] How do I know if my patient may have myeloma? How do I distinguish diabetes from myeloma? What testing should I do?”

Sikander Ailawadhi, MD, a professor of medicine in the Division of Hematology/ Oncology at Mayo Clinic in Jacksonville, Florida, noted in the discussion that addressing disparities in multiple myeloma is a multifactorial problem. “We can make the diagnosis, [but] how do we get the right treatment? How do we change the physician bias that the patient may not have money to afford that drug? How do we get the appropriate resources to the patient to overcome their social determinants, their poor social determinants, so that they are able to come in for that injection of bortezomib [Velcade]?” Access is not just based on availability of the agents, but on the surrounding social determinants of health that may affect a patient’s ability to get to the clinic for treatment that requires an in-office visit. “These are challenges of we are facing [and] what a patient facing,” he said.

Patient advocacy and education, an area of focus for cancer care identified by the American Association for Cancer Research, is another avenue Ailawadhi cited for clinicians to develop a knowledge base. “A smaller but significant piece [of the puzzle] is when patients receive a diagnosis, even those who come from larger cancer or academic centers, is that we must teach our patients, the fellows, the residents, the community,” he said. “Frequently, patients don’t have an understanding about their diagnosis. We all love to say, we want the patients empowered. We want the patients to be their own advocate. But if the patient doesn’t know what to ask, they’re not going to be able to do so.”

In breast cancer, disparities between outcomes for White women and Black women is an area where improvements have been pacing a relatively slower rate. “We hear a lot about these disparities, and we need to appreciate that the situation is still the same,” Bridget A. Oppong, MD, said in an interview with OncologyLive

. Oppong is deputy director of the Center for Cancer Health Equity at the Ohio State University Comprehensive Cancer Center (OSUCCC)–James and an associate professor in the Division of Surgical Oncology at The Ohio State University College of Medicine. “Although the overall population is doing better with breast cancer, there is still a 40% mortality difference [between White and Black women]. We have a lot of work to do to ensure that we can provide care in an equitable fashion so that this disparity can be reduced…. Addressing these disparities begins with knowledge and awareness.”

Oppong noted that cultural barriers and stereotypes are barriers facing minority women in screening and that even if early detection is achieved, access remains a concern. “We need to think about things such as Medicaid expansion, where we can increase the number of [individuals] who may be underinsured to get that screening. Additionally, we need to ensure that we continue funding things such as breast and cervical cancer programs to encourage screening.”

Education about delays in treatment is another area that Ailawadhi noted will be of importance. “Although I cannot change a patient’s insurance or the access to a drug, [one thing] I can do is make sure a physician is aware that if they don’t treat the patient [in a] timely [fashion], the patient is going to have more morbidity,” he said. This also comes with advocating for a patient to have consults or access to academic centers whenever possible. “Patients need to stay and get treated where they are. They have their infrastructure, their social support system, their caregiver, their circle of care. But if they get a consult [at an institution], they’re going to be more empowered. They’re going to get more knowledgeable. They need to know about [available] drugs.”

Genomic analysis has come into the spotlight as targeted therapies have become more readily available for patients. In a retrospective analysis of solid and liquid biopsy samples submitted for broad-panel genomic analysis to Foundation Medicine, the predominant ancestry of patients was European (75.6%), reflecting underserved racial and ethnic groups in the testing pool. The analysis, which collected data from 2013 to 2022, noted that in the first 12 months of the study 11,827 samples were submitted for nextgeneration testing (NGS) compared with 96,360 submitted in the last year. In the 9-year period, the number of African ancestries increased by nearly 0.5 percentage points annually, ending at 12.4% of persons who underwent genomic testing by 2022.

Awareness and accessibility of clinical trials has been a slow pathway to establish between community and institutional research. With recent studies citing enrollment rates of approximately 4% for patients treated in community sites, a physician-reported analysis of barriers to enrollment have highlighted the complexity of facilitating patient enrollment from multiple levels.

Oppong said that she actively works to normalize research and scientific investigation for her patients and the among the Black community. 

“The only way to answer questions [about genetic differences in breast cancer] is through research. The only way to know if Black women’s cancers are genetically somehow different from those of White women is through research. We have work to do in increasing enrollment when it comes to minorities, especially African Americans.” 

A renewed focus on dismantling the barriers and closing gaps in care will aid in the mission to drive down the rate of cancer mortality and incidence across disease states. 

2023 Cancer Trends Highlight Opportunities to Close Gaps in Care in Community Practice 

Although invasive lobular carcinoma (ILC) is the second most-common subtype of breast cancer, the understanding of the clinical implications of its distinct pathological and genomic profile remains a work in progress. Research groups in the United States and Europe are seeking to build the knowledge base about ILC in hopes that therapy can be tailored for patients with this diagnosis.

Outcomes among patients with ILC may differ from those for patients with invasive ductal carcinoma (IDC), the most common breast cancer subtype, with frequently used treatment regimens. Neoadjuvant chemotherapy is not effective for carcinomas classified as purely lobular and these patients should not be offered this approach routinely, according to Sibylle Loibl, MD, PhD. Upfront therapy with an aromatase inhibitor (AI) may be beneficial for patients with hormone receptor–positive ILC, Loibl said.

Loibl, chair of the German Breast Group, shared her insights on ILC during the 2022 San Antonio Breast Cancer Symposium (2022 SABCS) in December. She is CEO of the GBG Forschungs GmbH in Neu-Isenburg and an associate professor of obstetrics and gynecology at Goethe University Frankfurt, both in Germany.

Loibl’s presentation was one of more than 20 posters, abstracts, and discussions about ILC at 2022 SABCS, a sign of the growing awareness of the tumor subtype and of advocacy efforts to improve understanding about it.

 She noted several ongoing studies testing treatment strategies in cohorts that include patients with ILC (Table).

Moving forward, the distinctive genomic profile of ILC may warrant changes in testing strategies, according to Loibl. “Some of the genomic alterations are associated with endocrine resistance and might play a role in today’s modern treatment options,” she said.

“When we look at invasive lobular carcinoma, we might consider testing those patients more often. We might find more mutations and also more mutations that play a role in endocrine- resistant pathways.” 

Lobular carcinoma as a distinct subtype of breast cancer was first described in 1941 as an in situ carcinoma in isolated cells or groups of cells in the lobule or terminal lobular duct.

 Today, lobular carcinoma in situ is classified as a benign entity whose presence indicates an elevated risk of breast cancer; risk-reduction endocrine therapy is the preferred approach for most individuals.

In contrast, 10% to 15% of all breast cancers (approximately 40,000 cases annually in the United States) are ILC, making it the second most common subtype after IDC.

 The incidence of ILC increased from 1987 to 1999, possibly because of improved diagnostic techniques and the use of combined hormone replacement therapy. However, a sharp decrease in the use of hormone replacement therapy did not translate into a marked decline in ILC; the rates decreased from 2002 to 2006, but not significantly.

In terms of histology, ILC is among 20 subtypes of breast cancer defined by their distinct biological features, according to Jorge S. Reis-Filho, MD, PhD, FRCPath, director of the experimental pathology service at Memorial Sloan Kettering Cancer Center in New York, New York, and co-administrative core director of its Specialized Programs of Research Excellence in Genomic Instability in Breast Cancer. Although these other subtypes are often called “special types” of breast cancer, the diagnosis of the predominant IDC subtype is made after the pathologist “has ruled out all the other histologic subtypes,” Reis-Filho said during a presentation at 2022 SABCS.

“Special histologic types of breast cancer have not only distinct histologic appearances but also different genomic features and biological characteristics. Understanding these tumors and subtyping them can be challenging. Subtyping does indicate different biology and, likely going forward, different therapeutic approaches.” 

The histologic characteristics of ILC include monomorphic cells, single cell files, intracytoplasmic lumina, round nuclei, and varying degrees of atypia, with more than 85% classified as grade I or II. Delving deeper into the subtype, ReisFilho described 8 variants of ILC: classic, alveolar, trabecular, solid, mixed, pleomorphic, histiocytoid, and signet ring.

More than 90% of ILCs are estrogen receptor (ER)– or progesterone receptor–positive, are HER2 negative, and have a low Ki67 proliferation index.8 Metastases are more likely to occur in the gastrointestinal tract, ovary, peritoneum, and bone, and less likely to affect the lungs.

The tumors are distinguished by a loss of E-cadherin, a transmembrane glycoprotein encoded by the 

gene with varied roles in the processes of cell migration and invasion.

 The adhesion molecule is essential to the maintenance of cell viability, and its dysregulation results in the distinctive growth patterns evident in ILC.

 Inactivation of E-cadherin is associated with ILC as well as atypical lobular hyperplasia and lobular carcinoma in situ.

 have been observed in approximately 80% of ILCs.

 aberrations have been detected in approximately 65% of ILC specimens, followed by

ake up more than 50% of the aberrations in ILC, suggesting that AKT inhibition might have a place in the treatment algorithm.

There also are genomic differences in the profiles of ILC variants; pleomorphic ILC, a less common but more aggressive subtype, had a higher frequency of 

Investigators have found that clinical characteristics of patients with ILC also differ from those of patients with IDC. In November 2022, Steffi Oesterreich, PhD, and colleagues published findings from a large retrospective study of women treated for breast cancer from 1990 to 2017 at the University of Pittsburgh Medical Center in Pennsylvania, Cleveland Clinic in Ohio, and The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.

Oesterreich is Shear Family Foundation Chair in Breast Cancer Research, professor and vice chair in the Department of Pharmacology and Chemical Biology at University of Pittsburgh School of Medicine, and co-director of Women’s Cancer Research Center at Hillman Cancer Center, Magee Women’s Research Institute. She also is former chair of the scientific advisory board of the Lobular Breast Cancer Alliance (LBCA), an advocacy group.

Among 33,662 patients included in this Great Lakes Breast Cancer Consortium analysis, 10.7% had ILC and 89.3% had IDC. Patients with ILC were older at diagnosis than those with IDC (aged 61 years vs aged 57 years, respectively). Patients with ILC vs those with IDC were more likely to have tumors classified as grades 1 and 2 (88% vs 60%, respectively), more frequently classified as stages III and IV (20.7% vs 10.4%), and more often diagnosed with de novo metastatic disease stage IV disease (3.7% vs 2.4%).

Moreover, patients with ILC had tumors that were larger in size than patients with IDC, with 14.7% at T3 and T4 vs 4.0%, respectively, and had more nodal involvement, with 9.9% vs 5.5% having N2 and N3 tumors at diagnosis. ILC tumors also were more likely than IDC malignancies to be ER positive (96% vs 77%, respectively) and progesterone receptor–positive (81% vs 67%, respectively).

Patients with ILC are candidates for the same treatment regimens as those with IDC, according to National Comprehensive Cancer Network guidelines.5 In the Great Lakes Breast Cancer Consortium data set, patients with ILC were less likely than those with IDC to receive radiation therapy (52% vs 57%, respectively) and chemotherapy (44% vs 47%) and more like to receive hormonal therapy (78% vs 61%). Mastectomy rates were significantly higher among patients with ILC compared with those with IDC (60% vs 50%, respectively).

Although the same treatment strategies are used for patients with ILC and IDC, differences in outcomes have emerged. In the Great Lakes Breast Cancer Consortium data set, there was no difference in disease-free survival (DFS) when patients in the entire cohort were compared by subtype, but overall survival (OS) was significantly worse for patients with ILC (HR, 1.17; 95% CI, 1.09-1.25; P < .001).

Of note, both DFS and OS were significantly worse for patients with ILC vs those with IDC in cohorts with ER-positive, HER2-negative breast cancer. The HRs were 1.18 for DFS (95% CI, 1.011.38; P = .03) and 1.32 for OS (95% CI, 1.19-1.45; P < .001). Additionally, the probability of DFS diverged between the 2 subtypes over a 20-year period, showing an increase of late recurrences among patients with ILC vs those with IDC.

Other studies have shown a similar deterioration in outcomes for patients with ILC over time. Patients with ILC had an early advantage over those with IDC in DFS and OS, according to a 2008 analysis of findings from 15 International Breast Cancer Study Group trials. The curves started to diverge after 6 years for DFS and after 10 years for OS, when an advantages began to emerge for IDC. After 6 years, the risk of a DFS event was 54% higher for patients with ILC vs those with IDC (HR, 1.54; 95% CI, 1.31-1.81; P < .01). After 10 years, the risk of death was 50% higher for patients with ILC (HR, 1.50; 95% CI, 1.22-1.86; P < .01). The pattern was similar regardless of ER status.

In a more recent study, investigators analyzed outcomes among 171,881 patients with breast cancer, approximately 84.2% of which had IDC, 9.6% had ILC, and 6.3% had a mixed invasive ductal and lobular carcinoma histology. The findings showed that OS was better for patients with ILC or mixed histology than for those with IDC, with HRs of 0.84 (95% CI, 0.77-0.90) and 0.91 (95% CI, 0.83-1.00), respectively.

However, Loibl noted during her presentation that the follow-up period of this study, at less than 6 years, is shorter than the longer periods of time analyzed in the earlier research. 

Although recommendations for treating patients with ILC often are similar to those for IDC, investigators are seeking to determine whether therapy choices should take histology into account.

 During her 2022 SABCS presentation, Loibl sorted through study results for several strategies, noting that the data at times provide a mixed verdict on optimal treatments for ILC.

Although neoadjuvant chemotherapy frequently is used for patients with substantial nodal involvement, this approach has mixed results for patients with ILC. In 2014, Loibl and colleagues showed that pathologic complete response (pCRs) rates were significantly lower for patients with ILC vs those with non-ILC histology in 9020 patients with breast cancer treated during neoadjuvant trials in Germany (6.2% vs 17.4%, respectively; P < .001).

However, the pCR rate differed for patients with ILC when analyzed by tumor grade and hormone receptor status. The pCR rates were 4.2% among patients with ILC hormone receptor–positive, grade 1 or 2 tumors; 7.0% in ILC hormone receptor–positive, grade 3 tumors or hormone receptor–negative, grade 1 or 2 tumors; and 17.8% in ILC with hormone receptor–negative, grade 3 tumors. OS was higher among patients who achieved pCR in ILC and non-ILC groups.

By comparison, adjuvant chemotherapy showed a benefit in findings from a retrospective study of 2318 patients with hormone receptor–positive, HER2-negative ILC who received primary surgery followed by endocrine therapy with or without chemotherapy.

The addition of chemotherapy demonstrated improved outcomes for patients who received combination therapy (n = 823) compared with those who had endocrine therapy alone (n = 1485). The HRs favoring combination therapy were 0.61 for DFS (95% CI, 0.41-0.90; P = .01) and 0.52 for OS (95% CI, 0.31–0.87; P = .01). However, subgroup analysis showed that patients with low-risk disease did not significantly benefit from the addition of chemotherapy.

One of the more interesting therapeutic questions involves adjuvant endocrine therapy for patients with ILC, because mixed results have been reported in several large clinical trials, Loibl said. The phase 3 TEAM trial (NCT00036270) compared the AI exemestane with tamoxifen, a nonsteroidal selective estrogen receptor modulator, as endocrine therapy, followed by exemestane for postmenopausal women with hormone receptor–positive nonmetastatic breast cancer. A comparison of participants by histology showed similar rates of relapse-free survival for patients with ILC and those with IDC.

However, data from the phase 3 BIG 1-98 study (NCT00004205) indicated a greater benefit with letrozole, an AI inhibitor, compared with tamoxifen in patients with early-stage classic ILC or IDC, with differences in treatment effect associated with histology.

The 8-year estimate for DFS was 66% with tamoxifen vs 82% with letrozole in patients with ILC (HR, 0.48; 95% CI, 0.31-0.74). Among patients with IDC, the DFS rate was 75% for tamoxifen and 82% for letrozole (HR, 0.80; 95% CI, 0.68-0.94). Similarly, the OS rate was 74% for tamoxifen vs 89% for letrozole in the ILC cohort (HR, 0.40; 95%CI, 0.23-0.69) and 84% for tamoxifen vs 88% for letrozole in the IDC group (HR, 0.73; 95% CI, 0.60-0.89).

In this trial, DFS and OS rates also were associated with histology for the luminal A–like and luminal B–like subtypes. For ILC, HRs favored letrozole for patients with both luminal Alike (HR, 0.50) and luminal B–like (HR, 0.34) subtypes, whereas in IDC, an advantage was observed for luminal B–like group (HR, 0.65) but not the luminal A–like cohort (HR, 0.95).

“The BIG 1-98 trial was the first trial indicating that there might be a higher benefit for an up-front aromatase inhibitor in patients who have lobular carcinoma,” Loibl said. “This was, for awhile, thought to be the standard of care.... It was actually the first treatment decision made based on the histologic subtype for the patient.”

The findings, however, were not repeated in the ABCSG 8 trial (NCT00291759), which evaluated outcomes among postmenopausal women with hormone receptor–positive early breast cancer who received adjuvant therapy with tamoxifen for 2 years, followed by either tamoxifen or anastrozole for 3 years. In the overall population, there was no significant difference in DFS and OS in terms of ILC and IDC, Loibl said. However, when results were analyzed by luminal status, investigators observed a greater benefit in the ILC cohort for luminal B subtype with anastrozole vs tamoxifen for DFS (HR, 0.35) than in the IDC luminal B group (HR, 0.86) and for OS (HR, 0.32 vs 1.09, respectively).

In terms of immunotherapy, the first clinical study designed for patients with ILC, the GELATO trial (NCT03147040), was terminated prematurely after failing to show sufficient benef it, Loibl noted. The study evaluated combination therapy with atezolizumab (Tecentriq), a PD-L1 inhibitor, plus carboplatin in patients with metastatic ILC. The objective response rate in 21 evaluable patients was 19% (95% CI, 5%-42%), with a median duration of response of 12 weeks (95% CI, 7.1-not reached).

Although several prospective studies are testing treatment strategies for patients with ILC, investigators cite a range of outstanding questions that should be explored. 

An improved understanding of the tumor microenvironment in ILC is among the most pressing research questions.

 Other questions involve whether there is “a greater propensity for tumor dormancy” in ILC, as suggested by the Great Lakes Breast Cancer Consortium findings, according William J. Gradishar, MD.

“Long-term follow-up and novel therapeutic strategies are required for [patients with ILC],” wrote Gradishar, chief of Hematology and Oncology in the Department of Medicine and the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. 

LBCA and other groups are seeking to raise awareness about ILC and advance a research agenda into the subtype. At 2022 SABCS, investigators reported results from a survey of practicing oncologists, researchers, patients, and advocates.

Only 46% of clinicians (n = 413), mostly medical oncologists and surgeons, and 48% of researchers (n = 376) said they felt confident in being able to describe the differences between ILC and breast cancer of no special type. Respondents identified the most important research questions for the ILC field as determining mechanisms of endocrine resistance and identifying novel therapeutic targets, repurposing existing drugs, and testing them in clinical trials.

The survey was an international collaboration developed with input from breast cancer clinicians and researchers, laboratory-based researchers, and advocates and patients led by Oesterreich and Leigh Pate, an ILC survivor who founded LBCA. Pate died of complications from ovarian cancer in June 2022. Laurie Hutcheson, MS, executive director of LBCA, and Flora Migyanka, chair of The Dynami Foundation and an LBCA patient advisory board member, were among many investigators and clinicians contributing to the research.

In responding to the survey, only 46% of clinicians (n = 413), mostly medical oncologists and surgeons, and 48% of researchers (n = 376) said they felt confident in being able to describe the differences between ILC and breast cancer of no special type. Respondents identified the most important research questions for the ILC field as determining mechanisms of endocrine resistance and identifying novel therapeutic targets, repurposing existing drugs, and testing them in clinical trials.

At 2022 SABCS, the LBCA reported findings from the organization’s survey of patients diagnosed with metastatic ILC. A total of 241 patients submitted complete responses; 77% of respondents live in the United States or Canada.

Overall, 48% of respondents said their metastatic ILC diagnosis was an unexpected or incidental finding during another medical procedure. For 41% of respondents, the diagnosis of metastatic ILC was de novo.

Additionally, 36% said at least 1 imaging modality had failed to detect 1 or more of their metastatic sites at diagnosis; 54% of respondents with bone metastases and 19% of participants with gastrointestinal metastases said their metastatic sites were not depicted on standard imaging.

Investigators said the findings show that early detection of ILC is challenging, and that routine breast cancer screening methods may not be sensitive enough to detect ILC.

Loibl S. Challenging types of breast cancer: lobular/pleomorphic. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

ILC science and patient advocacy well represented at SABCS22. Lobular Breast Cancer Alliance. December 14, 2022. Accessed January 21, 2023. 

Foote FW, Stewart FW. Lobular carcinoma in situ: a rare form of mammary cancer. 

Research groups in the United States and Europe are seeking to build the knowledge base about invasive lobular carcinoma in hopes that therapy can be tailored for patients with this diagnosis.

Vol. 24/No. 3 | Oncology Live®

Slow Burn to Wildfire: How Do We Douse the Flames of Burnout in Oncology?

EPCORE Pushes CD3 × CD20 Bispecific Antibody Into Next Phase of Exploration in DLBCL

2023 Cancer Trends Highlight Opportunities to Close Gaps in Care in Community Practice

Invasive Lobular Carcinoma Comes Into Sharper Focus

Multifaceted Approach Remains a Linchpin for Stage IIIB NSCLC Therapy

Barriers to Confirmatory Trial Enrollment Present Unique Hurdles for Accelerated Approvals