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A chatbot-based approach was found to be equivalent to standard-of-care (SOC) approaches in terms of the completion of pretest cancer genetic services and genetic testing among individuals who were eligible for cancer genetic testing, according to data from the interventional BRIDGE trial (NCT03985852).

 demonstrated that individuals in the chatbot group (n = 1554) and the SOC group (n = 1519) completed genetic testing (12.3% vs 13.6%) and completed pretest genetic services (25.7% vs 23.8%), representing respective estimated differences of –1.3% (95% CI, –3.7% to 1.1%; 

 = .002) and 2.0% (95% CI, –1.1% to 5.0%; 

 < .001). Patients in both arms also ordered genetic testing (15.0% vs 18.1%) and began pretest services (31.0% vs 29.2%) at similar rates, conferring estimated differences of –3.1% (95% CI, –5.7% to –0.5%; 

 = .16) and 1.7% (95% CI, –1.5% to 5.0%; 

“There’s greatly increasing demand for pretest cancer genetic services for unaffected patients, [including individuals] who might not be seen in a cancer center as a part of a diagnosis but have a family history of cancer suggesting that they may be eligible for cancer genetic testing,” Kimberly Kaphingst, ScD, the lead author of BRIDGE, said in an interview with 

. “The rationale [for BRIDGE] was to test whether we could use a chatbot as part of a genetic counseling workflow to supplement the role of certified genetic counselors, saving their time for the return of the complicated results, the pathogenic findings, and so forth with the chatbot by doing some of the automated education.”

Kaphingst is the director of cancer communication research as well as a professor and an associate chair in the Department of Communication at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

BRIDGE was an equivalence trial conducted from August 2020 to August 2023. The study enrolled patients aged 25 to 60 years who underwent a primary care visit in the University of Utah Health or NYU Langone Health systems over the prior 3 years. Patients needed to be eligible for cancer genetic testing according to the modified National Comprehensive Cancer Network guidelines based on their family history in the electronic health record (EHR). To be included in the study, patients also had to speak English or Spanish, had not received prior cancer diagnoses other than nonmelanoma skin cancer, and had not undergone previous genetic counseling or testing related to hereditary cancer.

A pool of eligible patients was identified using GARDE, an open-source platform that extracts and examines information related to family history of cancer from the EHR. Eligible patients were randomly assigned 1:1 to the chatbot intervention group or the enhanced SOC control group.

In the chatbot intervention group, patients received a patient portal message recommending genetic services that included a hyperlink to pretest genetics education administered via chatbot. The chatbot used text, images, and video to convey key information delivered during SOC pretest genetic counseling appointments. After a video message from the lead genetic counselor at the patient’s center, the patient progressed through a core set of scripted information and was able to ask for additional information on predetermined topics or ask open-ended questions; open-ended questions that did not have a scripted response were emailed to the genetic counseling team.

Patients received a reminder message in 1 week in the event of an incomplete chat in addition to up to 2 follow-up calls from a genetic counseling assistant. At the end of the script, patients were offered the choice to continue with genetic testing and were then contacted by a genetic counseling assistant to confirm their decision and collect additional information.

“The chatbot that we tested in this study was an entirely scripted, rules-based chatbot, which is designed to have interactive conversations with patients,” Kaphingst explained. “It is artificial intelligence [AI] enabled, so it was able to answer questions using a natural language processing part of the platform. It did not [use] any generative AI.”

In the enhanced SOC group, patients received a patient portal message that recommended they receive genetic services, encouraging them to contact the genetics clinic at their site to schedule a pretest genetic counseling appointment. Those who did not respond received a reminder message a week later and 2 follow-up calls from a genetic counseling assistant. Patients who were interested in and eligible for an appointment were scheduled for one with a certified genetic counselor; most appointments were performed via telephone.

Samples from patients in both arms who opted for genetic testing were analyzed via pan-cancer, multigene panels for cancer susceptibility of approximately 34 to 36 genes. The primary outcomes of BRIDGE were the completion of pretest cancer genetic services, such as a pretest genetics education discussion or the scheduling of a pretest genetic counseling appointment, and the completion of genetic testing. Secondary outcomes included initiating pretest cancer genetic services and ordering genetic testing.

The baseline patient characteristics were well balanced between the chatbot and SOC arms; the mean patient ages were 43.5 years (range, 26-63) and 44.1 years (range, 26-63), respectively. Most patients in both groups were female (74.1% vs 71.7%) and White (74.9% vs 75.1%), spoke English (98.6% vs 98.8%), were seen at NYU Langone Health (53.0% vs 53.1%), and resided in an urban area (96.3% vs 96.5%).

Additional findings from BRIDGE revealed that patients in the chatbot (n = 731) and SOC (n = 713) groups from the University of Utah Health system completed genetic testing (14.2% vs 14.2%), completed pretest genetic services (28.0% vs 26.5%), ordered genetic testing (17.2% vs 20.9%), and began pretest services (33.2% vs 32.5%) at similar rates. In the NYU Langone Health system, the rates of completing genetic testing (10.6% vs 13.0%), completing pretest genetic services (23.7% vs 21.3%), ordering genetic testing (13.0% vs 15.6%), and beginning pretest services (28.9% vs 26.3%) were also similar in the chatbot (n = 823) and SOC (n = 806) groups.

“Having these types of tools to help supplement the genetic counseling process is going to be extremely helpful,” Whitney F. Espinel, MS, CGC, a coauthor of BRIDGE from the Breast Cancer Risk Clinic at Huntsman Cancer Institute at the University of Utah, said in the interview. “We can help the traditional process [with] a pretest and a posttest counseling session. We can utilize chatbots [during the] pretest and cut out some of that need for the genetic counselor up front and still utilize our skills to interpret test results and connect patients to resources. There are lot of unique ways that we can implement [chatbots] to see more patients and expand access to populations we haven’t been able to access before.”

Expanding Chatbot Access to Additional Patient Populations

Kaphingst and her coinvestigators are planning several additional studies to further evaluate the utility of the chatbot investigated in BRIDGE for other patient populations. “We’re thinking about how to improve access to these sorts of automated tools for Spanish-speaking patients, patients who speak other languages, and to reach out to rural and frontier populations who may have more limited broadband access,” she said.

In January 2024, the Huntsman Cancer Institute announced that Kaphingst and her coinvestigators had received additional funding from the National Cancer Institute to study the chatbot in Spanish-speaking women.

“[This is] an area I’m enthusiastic about, because I think you can really incorporate chatbots into the places that individuals who may not speak English as a primary language much easier,” Espinel added. “We’re utilizing a cancer screening mobile clinic for that and there’s a lot of ways we can bring it to the community instead of them having to come to us, which is often a barrier [to care].”

Kaphingst KA, Kohlmann WK, Lorenz Chambers R, et al. Uptake of cancer genetic services for chatbot vs standardof- care delivery models: the BRIDGE randomized clinical trial. 

. 2024;7(9):e2432143. doi:10.1001/ jamanetworkopen.2024.32143

Using chatbots to advance Spanish-speaking patient outreach. News release. University of Utah Huntsman Cancer Institute. January 9, 2024. Accessed November 4, 2024. https://healthcare.utah.edu/huntsmancancerinstitute/ press-releases/2024/01/using-chatbots-advance-spanishspeaking- patient-outreach

Articles

A chatbot-based approach for pretest cancer genetic services was found to be equivalent to standard-of-care (SOC) methods in the BRIDGE trial. The study involved patients eligible for genetic testing, showing similar completion rates for genetic testing and pretest services between the chatbot and SOC groups. The chatbot provided automated education, potentially reducing the workload of genetic counselors. Future studies aim to expand chatbot access to diverse populations, including Spanish-speaking and rural communities, to improve accessibility and outreach in cancer genetic services.

A chatbot-based approach was equivalent to SOC pretest cancer genetic services and genetic testing among individuals eligible for cancer genetic testing.

AI-Enabled Chatbot Replicates Efficacy of SOC Approaches in Aiding Receipt of Cancer Genetic Testing

The tight junction protein claudin 6 (CLDN6) has emerged as a potential therapeutic target in multiple solid tumor types, prompting the development of CLDN6-targeted agents, including antibody-drug conjugates (ADCs) and a chimeric antigen receptor (CAR) T-cell agent that can be used in combination with an accompanying CAR cancer vaccine.

“CLDN6 is an important component of cell-to-cell tight junctions, [and] it plays a role in the regulation of epithelial and endothelial cell proliferation and differentiation,” Manish R. Patel, MD, director of drug development at Florida Cancer Specialists & Research Institute in Sarasota, Florida, said in an interview with 

. “It is nearly absent in normal adult tissue but is expressed in several tumor types, including ovarian, endometrial, gastric, and non–small cell lung cancer [NSCLC], as well as germ cell tumors. There are also a lot of data [that show CLDN6 expression] can be associated with poor prognosis.”

CLDN6 is one of 27 CLDN family proteins and is located on chromosome 16p13.3.

It has 4 transmembrane domains and a PDZ-binding region at the carboxyl end of the cytoplasm. CLDN6 can bind with signal proteins and cytoskeletal proteins, allowing it to participate in the cellular response to external and intracellular signal transmission. Notably, it is the only CLDN protein to display potential specificity to activate cell adhesion signals and regulate the activity of nuclear receptors.

During the 2024 European Society for Medical Oncology (ESMO) Congress, investigators presented findings from 3 phase 1 studies evaluating CLDN6-directed agents that showed signals of promising efficacy and tolerability, underscoring the value of the protein as a potential therapeutic target in gynecologic malignancies and other tumor types.

CLDN6-Targeted ADCs Display Single-Agent Activity

Patel presented findings from a first-in-human phase 1 study (NCT05394675) examining DS-9606 monotherapy in patients with advanced or metastatic solid tumors known to express CLDN6, although CLDN6 expression was not required for enrollment.

 “DS-9606 is an ADC composed of a humanized anti-CLDN6 monoclonal antibody with a cleavable linker to a modified pyrrolobenzodiazepine [PBD] payload,” Patel explained.

Eligible patients in the dose-escalation phase needed to experience disease progression on standard-of-care therapies for metastatic disease, have an ECOG performance status of 1 or less, have received no prior CLDN6-targeted agents or ADCs that deliver a PBD payload, and have adequate cardiac and pulmonary function, including no history of or current interstitial lung disease/pneumonitis. During the dose-escalation phase, patients received intravenous DS-9606 every 3 weeks at dose levels ranging from 0.016 mg/kg to 0.225 mg/kg. The study population (n = 53) included patients with ovarian cancer (35.8%), germ cell tumors (20.8%), gastric/gastroesophageal junction (GEJ)/esophageal adenocarcinoma (13.2%), NSCLC (13.2%), pancreatic cancer (9.4%), breast cancer (3.8%), and endometrial cancer (3.8%).

At the June 14, 2024, data cutoff, preliminary efficacy findings from the study demonstrated that the response was highest with the 0.150-mg/kg dose, with 3 of 12 patents achieving a confirmed objective response per RECIST 1.1. Four patients—2 with germ cell tumors, 1 with NSCLC, and 1 with gastric/GEJ/esophageal adenocarcinoma—experienced an objective response per RECIST 1.1.

Among patients with germ cell tumors (n = 7), the 2 responders achieved a partial response (PR) per RECIST 1.1 and remained on treatment for more than 6 months. Most of these patients (n = 5) had a reduction in tumor markers of at least 90%.

“In terms of efficacy, these were some promising results,” Patel said. “There were 4 confirmed PRs, but there were [also] other patients who had reduction of disease, and there were several patients who had reduction of their blood tumor markers. When you look at the waterfall plot and dive into the germ cell tumor responses, those are very interesting.”

Regarding safety, no dose-limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) and recommended dose for expansion were not yet determined (Table).

 Across dose levels, any-grade treatment-emergent adverse effects (TEAEs) occurred in 84.9% of patients, with 52.8% being deemed related to treatment. Grade 3 or higher and serious TEAEs were reported in 30.2% of patients each. There were no grade 5 TEAEs, and the most common any-grade TEAEs included nausea (18.9%), fatigue (18.9%), and anemia (17.0%).

“At the data cutoff, there were no cases of pneumonitis, and all the AEs after that data cutoff were mostly low-grade cutaneous toxicities,” Patel said. “In terms of the future, dosing continues. The dose hasn’t been declared yet, but once it is there, there are plans to focus on some of these tumor types in further enrollment, either in this trial or in other trials; that’s to be determined.”

Results of another first-in-human, phase 1 study (NCT05103683) were presented during the 2024 ESMO Congress. In the trial, investigators are evaluating TORL-1-23, a novel CLDN6-directed ADC in patients with advanced solid tumors.

 The study included patients with ovarian (n = 14), testicular (n = 1), and endometrial cancers (n = 6), as well as NSCLC (n = 6) and other tumor types (n = 3). The primary objectives were to determine the safety, tolerability, DLTs, MTD, and recommended phase 2 dose of TORL-1-23 monotherapy.

“TORL-1-23 has a very high specificity for CLDN6,” Gottfried E. Konecny, MD, the presenting author of the study, said in an interview with 

“There are many CLDN proteins, but it doesn’t cross-react with other CLDNs. This has been shown on a laboratory level, which is very important because the homology [with] CLDN6 is very high. Some of [the proteins] only differentiate each other by a few amino acids. I believe we can safely say that it’s a very specific antibody for CLDN6. It has a cleavable linker and microtubule inhibitor as a payload, monomethyl auristatin, which is in clinic in a number of other ADCs that are approved already.”

Konecny is the lead clinician for gynecologic oncology in the Department of Medicine at UCLA Health in Los Angeles, California.

Preliminary efficacy data from the trial revealed that there was activity in 73% of patients treated across dose levels and tumor types. Patients receiving the 0.2- to 2.0-mg/kg dose (n = 19) achieved an objective response rate (ORR) of 26%; those who received TORL-1-23 at the 2.4-mg/kg (n = 19) or 3.0-mg/kg dose levels (n = 26) experienced ORRs of 42% and 31%, respectively.

Notably, patients with CLDN6-positive platinum-resistant ovarian cancer treated with the 2.4-mg/kg dose (n = 8) achieved an ORR of 50%, and those treated at the 3.0-mg/kg dose (n = 12) experienced an ORR of 42%. The preliminary median duration of response (DOR) among these patients was approximately 22 weeks and approximately 30 weeks at the 2.4-mg/kg and 3.0-mg/kg dose levels, respectively.

In terms of safety, patients across tumor types receiving the 0.2- to 2.0-mg/kg dose (n = 19) experienced any-grade AEs including fatigue (26%) neuropathy (26%), anemia (11%), neutropenia (11%), nausea (11%), diarrhea (11%), and alopecia (11%). At the 2.4-mg/kg dose (n = 6), patients experienced any-grade alopecia (67%), anemia (50%), and neutropenia (50%). Any-grade AEs in the 3.0-mg/kg dosing group (n = 11) included anemia (64%), fatigue (64%), and alopecia (64%). In the dose-expansion part, patients who received TORL-1-23 at the 2.4-mg/kg dose level (n = 16) experienced any-grade AEs including nausea (67%), fatigue (56%), and alopecia (56%).

Determination of the MTD was ongoing at the time of data cutoff. A registrational phase 2 study of TORL-1-23 in patients with CLDN6-positive platinum-resistant ovarian cancer is being initiated, and the agent is also under evaluation in other CLDN6-positive cancers, including NSCLC.

CLDN6 Shows Potential as mRNA Vaccine, CAR T-Cell Therapy Component

Beyond being used as a therapeutic target in the development of ADCs, CLDN6 is also being examined as a target for a novel CAR T-cell agent in combination with a CAR vaccine.

 In a first-in-human phase 1 study (NCT04503278), the investigational candidate BNT211 is combining these 2 approaches for the treatment of patients with relapsed/refractory CLDN6-positive solid tumors. Eligible patients needed to have at least 50% of tumor cells express CLDN6 via an immunohistochemistry score of 2+/3+, measurable disease per RECIST 1.1 or an elevated tumor marker, and an ECOG performance status of 1 or 0.

In part 1 of the dose-escalation phase, patients received CLDN6 CAR T-cell monotherapy. In part 2, the CAR T-cell component was combined with the CAR vaccine. The primary end points were safety and tolerability. Secondary end points included ORR, disease control rate (DCR), and DOR.

Preliminary efficacy data shared during the 2024 ESMO Congress showed that response-evaluable patients (n = 64) in the overall population (n = 74) achieved an ORR of 32.8% (95% CI, 18.5%-40.1%), including 3 patients with a complete response. The DCR was 67.2% (95% CI, 46.1%-69.5%). Response-evaluable patients who received the CAR T-cell agent at a dose of at least 1 × 10

cells with 100% lymphodepletion in combination with the CAR vaccine (n = 33) achieved an ORR and DCR of 51.5% (95% CI, 26.3%-57.9%) and 84.8% (95% CI, 51.9%-81.9%), respectively.

Efficacy-evaluable patients with testicular cancer (n = 25) in the overall population (n = 27) achieved an ORR of 24.0% (95% CI, 8.6%-42.3%) and a DCR of 56.0% (95% CI, 32.0%-71.3%). Evaluable patients (n = 12) who received the CAR T-cell agent at a dose of at least 1 × 10

 cells with 100% lymphodepletion in combination with the CAR vaccine (n = 14) experienced an ORR of 41.7% (95% CI, 12.8%-64.9%) and a DCR of 75.0% (95% CI, 35.1%-87.2%).

Efficacy-evaluable patients with ovarian cancer (n = 24) in the overall population (n = 30) achieved an ORR of 33.3% (95% CI, 12.3%-45.9%) and a DCR of 75.0% (95% CI, 40.6%-77.3%). Evaluable patients (n = 12) who received the CAR T-cell agent at a dose of at least 1 × 10

 cells with 100% lymphodepletion in combination with the CAR vaccine (n = 16) experienced an ORR of 58.3% (95% CI, 19.8%-70.1%) and a DCR of 83.3% (95% CI, 35.4%-84.8%).

In terms of safety, all patients who received CAR T-cell monotherapy and the vaccine-containing combination (n = 78) experienced an any-grade TEAE. Most patients also experienced a grade 3 or higher TEAE (91.0%), a serious AE (57.7%), any-grade treatment-related AEs (TRAEs; 92.3%), and grade 3 or higher TRAEs (66.7%). DLTs and TEAEs leading to treatment discontinuation occurred at rates of 9.0% and 2.6%, respectively.

“CAR T-cell therapy in solid tumors is fraught with high toxicity and, in some cases, mortality,” Konecny said. “There is a clear limitation based on the complexity, toxicity, and cost of this approach. But [the drug’s developer] may have the bandwidth to make it more cost-efficient and possibly safer. I am looking forward to [additional] data. They are expanding beyond platinum-resistant ovarian cancer, with male germ cell tumors particularly of interest.”

Du H, Yang X, Fan J, Du X. Claudin 6: therapeutic prospects for tumours, and mechanisms of expression and regulation (review). 

. 2021;24(3):677. doi:10.3892/mmr.2021.12316

Patel MR, Hamilton EP, Piha-Paul SA, et al.Preliminary results from a phase I, first-in-human study of DS-9606a, a claudin 6 (CLDN6)-directed antibody-drug conjugate (ADC), in patients (pts) with tumor types known to express CLDN6. 

. 2024;35(suppl 2):S488-S489. doi:10.1016/j.annonc.2024.08.677

Konecny GE, Wahner Hendrickson AE, Winterhoff B, et al. Phase I, two-part, multicenter first-in-human (FIH) study of TORL-1-23: a novel claudin 6 (CLDN6) targeting antibody drug conjugate (ADC) in patient with advanced solid tumors. 

. 2024;35(suppl 2):S551. doi:10.1016/j.annonc.2024.08.783

Haanen JBAG, Mackensen A, Schultze-Florey C, et al. Updated results from BNT211-01 (NCT04503278), an ongoing, first-in-human, phase I study evaluating safety and efficacy of CLDN6 CAR T cells and a CLDN6-encoding mRNA vaccine in patients with relapsed/refractory CLDN6+ solid tumors. 

. 2024;35(suppl 2):S489-S490. doi:10.1016/j.annonc.2024.08.678

Claudin 6 (CLDN6) is a promising therapeutic target in various solid tumors, including ovarian and non-small cell lung cancer, due to its expression in tumors and absence in normal adult tissues. Recent studies have explored CLDN6-targeted therapies, such as antibody-drug conjugates (ADCs) and CAR T-cell therapies, showing promising efficacy and tolerability. Phase 1 trials of DS-9606 and TORL-1-23 ADCs demonstrated objective responses in multiple tumor types. Additionally, CLDN6-targeted CAR T-cell therapy combined with a CAR vaccine showed potential in relapsed/refractory CLDN6-positive tumors.

Manish R. Patel, MD, and Gottfried E. Konecny, MD, detail findings from studies evaluating CLDN6-directed agents that showed signals of promising efficacy and tolerability.

CLDN6-Directed Agents Generate Encouraging Early Activity in Solid Tumors

The treatment landscape of newly diagnosed multiple myeloma has seen significant gains in 2024, headlined by the July 2024 FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd).

 Additional compelling data have also been reported from studies examining other combination regimens in the frontline setting, and multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated strong activity among patients with relapsed/refractory disease, leading to the expansion of their indications in this patient population by the FDA in 2024. 

“I am most excited about [the fact that] we have the diagnostics, the monitoring tools, and the treatments, and we are going to be able to use them in combination,” Thomas Martin, MD, said. “Start with a quadruplet and [also consider] immunotherapies, CARs, and bispecific [antibodies], and then stop treatment. That would be our definition of cure.”

During the 2024 International Myeloma Society (IMS) Annual Meeting, OncologyLive filmed a Peer Exchange onsite in Rio de Janeiro, Brazil, to obtain commentary from leading myeloma experts regarding impactful data updates that were presented during and around the meeting. The panelists discussed updated findings from clinical trials in newly diagnosed multiple myeloma, including the phase 3 PERSEUS (NCT03710603), CASSIOPEIA (NCT02541383), and IsKia (NCT04483739) studies. They also highlighted data from the phase 3 KarMMa-3 (NCT03651128) and CARTITUDE-4 (NCT04181827) studies, which are examining CAR T-cell therapies in relapsed/refractory multiple myeloma.

Quadruplets Hold Center Stage In Newly Diagnosed Multiple Myeloma

The PERSEUS study enrolled patients with transplantation-eligible, newly diagnosed multiple myeloma and randomly assigned them 1:1 to receive induction therapy with D-VRd followed by consolidation D-VRd and daratumumab and lenalidomide maintenance or induction and consolidation with VRd (bortezomib, lenalidomide, and dexamethasone) followed by lenalidomide maintenance therapy.

 The primary end point was progression- free survival (PFS); complete response (CR) or better, minimal residual disease (MRD)–negative status with a CR or better, and overall survival (OS) represented key secondary end points. Data from PERSEUS supported the July 2024 FDA approval of D-VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

At a median follow-up of 47.5 months (range, 0-54.4), data from the primary analysis of PERSEUS, which were published in the New England Journal of Medicine, demonstrated that patients who received D-VRd (n = 355) experienced a significant PFS benefit compared with those who received VRd alone (n = 354; HR, 0.42; 95% CI, 0.30-0.59; 

 The estimated 48-month PFS rates were 84.3% (95% CI, 79.5%-88.1%) in the D-VRd group and 67.7% (95% CI, 62.2%-72.6%), respectively. The CR or better rates were 87.9% and 70.1%, respectively (

 < .001) and the MRD negativity rates at a threshold of 10

“PERSEUS confirmed what everyone suspected after the [phase 2] GRIFFIN [NCT02874742] data came out [which was] the combination of daratumumab with bortezomib, dexamethasone, [and lenalidomide] has been a game changer for newly diagnosed myeloma,” Natalie Callander, MD, said. “The results [in terms of] response rate and 4-year PFS [rate] for PERSEUS have been amazing, really nothing else has come close.”

During the 2024 IMS Annual Meeting, investigators presented additional data from a cytogenetic risk analysis of PERSEUS.

 The median PFS favored the D-VRd arm vs the VRd arm across all cytogenetic risk subgroups, with the most pronounced improvements being reported in the isolated amp(1q21) (HR, 0.11; 95% CI, 0.01-0.87; 

 = .0115), revised standard risk (HR, 0.29; 95% CI, 0.15-0.56; 

 = .0001), and standard risk (HR, 0.35; 95% CI, 0.22-0.56; 

 < .0001) subgroups. Moreover, MRD negativity and sustained MRD negativity rates at thresholds of both 10

 favored D-VRd over VRd across all cytogenetic risk subgroups.

CASSIOPEIA is evaluating another daratumumab-containing quadruplet in patients with transplant-eligible, newly diagnosed multiple myeloma.

 During the consolidation phase of the study, patients were randomly assigned 1:1 to receive daratumumab with bortezomib, thalidomide (Thalomid), and dexamethasone (D-VTd) or bortezomib, thalidomide and dexamethasone (VTd). Patients with a partial response or better following the completion of the consolidation phase were eligible for the maintenance phase and underwent a second random assignment prior to this portion to receive daratumumab maintenance or observation only. The primary end point for the maintenance phase was PFS from second randomization; secondary end points included MRD negativity rate, CR or better rate, and OS.

At a median follow-up of 80.1 months, findings from CASSIOPEIA presented during the 2024 IMS Annual Meeting showed that the median PFS among patients who received D-VTd followed by daratumumab (n = 229) was not yet reached (NR) vs 72.1 months in the D-VTd followed by observation group (n = 229; HR, 0.76; 95% CI, 0.58-1.00; 

 In the VTd arm, patients who received daratumumab maintenance (n = 213) achieved a median PFS of NR compared with 32.7 months among those who received observation (n = 215; HR, 0.34; 95% CI, 0.26-0.44; 

 < .0001). The overall MRD negativity rates were 77.3% and 70.7% in the D-VTd arm with daratumumab maintenance or observation, respectively. These respective rates were 70.9% and 51.2% in the VTd arm.

“When you use the quadruplet, those are the patients who do the best,” Noopur Raje, MD, said. “We are seeing a deepening of MRD over time in patients who are continuing the consolidation as well as maintenance. CASSIOPEIA taught me that, because of the second randomization, as long as patients got daratumumab or an anti-CD38 monoclonal antibody, they did quite well and their PFS improved considerably, suggesting that as long as [patients] get daratumumab in their treatment algorithm, they’re going to do well, but the patients who did the best were the ones who were able to continue daratumumab from the start.”

“One of the controversies that still exists is do you use daratumumab just for induction, just for maintenance, or for both? My practice has been to use it before and after because [if I believe a patient is] going to relapse 8 or 9 years later, we’re not going to use daratumumab [at that point]. We’re going to have something new,” Martin added. 

In the phase 2 GMMG-CONCEPT study (NCT03104842), the quadruplet of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide, and dexamethasone (Isa-KRd) was evaluated in patients with transplant-eligible and transplant-ineligible, newly diagnosed, high-risk multiple myeloma.6 The primary end point was MRD negativity rate after consolidation and PFS represented the key secondary end point.

Four-year follow-up data presented during the 2024 IMS Annual Meeting demonstrated that transplant eligible patients (n = 127) achieved MRD negativity at any time point at a rate of 83.5%; patients sustained MRD negativity for more than 6 and 12 months at rates of 73.7% and 66.9%, respectively. Transplant-ineligible patients (n = 26) were MRD negative at any time point at a rate of 69.7% and achieved MRD negativity for over 6 and 12 months at rates of 57.7% and 50.0%, respectively. At a median follow-up of 54 months (range, 0-77.7), the 4-year PFS rate in the transplant-eligible group was 59.4% (95% CI, 51.7%-68.9%). In the transplant- ineligible group, at a median follow-up of 51 months (range, 0-67.7), the 4-year PFS rate was 54.3% (95% CI, 37.6%-78.3%). 

Isa-KRd is also being examined in IsKia, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma.7 Eligible patients were randomly assigned 1:1 to receive Isa-KRd induction and consolidation or KRd induction and consolidation. The primary end point was the rate of MRD negativity by next-generation sequencing following consolidation. MRD negativity after induction and PFS represented key secondary end points.

During the 2023 American Society of Hematology Annual Meeting, investigators presented initial data from IsKia which showed that patients in the Isa-KRd arm (n = 151) achieved an MRD negativity rate of 77% at a threshold of 10

 compared with 67% in the KRd arm (n = 151; OR, 1.67; 

, the MRD negativity rates were 67% and 48%, respectively (OR, 2.29;

 < .001). The MRD negativity rates at a threshold of 10

 post ASCT were 64% and 49%, respectively (OR, 1.93; 

“Looking at the PFS curves [in GMMGCONCEPT and IsKia], you see in the high-risk [subgroup] you can achieve MRD negativity, but you do see some relapses over time and there isn’t a plateau,” Martin said. “You really have to keep the pressure on. In other words, you can’t stop consolidation- or maintenance-based therapy. [These patients] need to have continuous maintenance.” 

The panelists concluded their discussion of frontline data updates in multiple myeloma by highlighting updated findings from CEPHEUS, which examined D-VRd vs VRd in patients with newly diagnosed multiple myeloma who are ineligible for ASCT or for whom transplant is deferred.

 Patients were randomly assigned 1:1 to receive D-VRd followed by maintenance with daratumumab, lenalidomide, and dexamethasone, or VRd with lenalidomide and dexamethasone maintenance. The primary end point was MRD negativity rate; key secondary end points included PFS, sustained MRD negativity, CR or better rate, and OS. 

During the 2024 IMS Annual Meeting, initial data from CEPHEUS were presented and showed that patients who received D-VRd (n = 197) achieved an MRD negativity rate of 60.9% at a 10

 threshold compared with 39.4% in the VRd arm (n = 198; OR, 2.37; 95% CI, 1.58-3.55; 

 < .0001). Patients sustained MRD negativity for at least 12 months at rates of 48.7% and 26.3%, respectively (OR, 2.63; 95% CI, 1.73-4.00; 

 < .0001). The respective CR or better rates were 81.2% and 61.6% (OR, 2.73; 95% CI, 1.71-4.34;

In September 2024, data from CEPHEUS supported the submission of a supplemental biologics license application to the FDA seeking the approval of D-VRd for the treatment of adult patients with newly diagnosed multiple myeloma for whom ASCT is deferred or those who are ineligible for ASCT.

“In this older patient population, the toxicity is not trivial, and the adverse effects [in terms of] infections in CEPHEUS were on the higher side,” Raje said. “In the real world, we don’t use the bortezomib twice a week except when [a patient] has high-burden and high-risk disease. I believe we can attenuate that toxicity but it’s something that we need to think about.” 

“Most patients can tolerate the quadruplet at least to start off with, and if they are poorly tolerated, you can always decrease either the dose or the frequency. But most patients, even those that would be qualified as transplant ineligible, can still tolerate quadruplets, as we’re seeing with all this transplant-ineligible data. I look forward to the day where we stop using transplant eligibility as the first fork in the road in newly diagnosed patients,” Adriana Rossi, MD, added.

CAR T-Cell Agents Offer Options for Patients With Relapsed/Refractory Disease

There are currently 2 FDA-approved CAR T-cell agents for the treatment of patients with relapsed/ refractory multiple myeloma: idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti). Ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma in March 2021, earning an indication for the treatment of patients following at least 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

 In February 2022, the FDA approved cilta-cel for the same patient population.

In April 2024, the FDA expanded the approval of ide-cel in multiple myeloma to include patients with relapsed/refractory disease following at least 2 prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

 The regulatory decision was supported by findings from KarMMa-3, which examined ide-cel vs standard regimens in patients with triple-class exposed relapsed/refractory multiple myeloma who received 2 to 4 prior regimens. The primary end point was PFS.

Updated findings from KarMMa-3 published in Blood demonstrated that patients who received ide-cel (n = 254) achieved a median PFS of 13.8 months compared with 4.4 months among those treated with standard regimens (n = 132; HR, 0.49; 95% CI, 0.38-0.63); the 18-month PFS rates were 41% and 19%, respectively.13 The median OS was 41.4 months (95% CI, 30.9-NR) vs 37.9 months (95% CI, 23.4-NR), respectively (HR, 1.01; 95% CI, 0.73-1.40). The ORR in the ide-cel arm was 71% (95% CI, 66%-77%), with a 44% stringent CR (sCR)/CR rate, compared with 42% (95% CI, 34%-51%), with a 6% sCR/CR rate, in the standard regimens arm. 

Following its initial FDA approval, cilta-cel was examined vs standard-of-care (SOC) regimens in patients with relapsed/refractory multiple myeloma following 1 to 3 prior lines of treatment, including a proteasome inhibitor and an immunomodulatory agent, in CARTITUDE-4.

 The primary end point was PFS; secondary end points included CR or better rate, ORR, MRD negativity, and OS. Updated findings from the study were presented during the 2024 IMS Annual Meeting.

“Long-term toxicities are something we need to think about [with CAR T-cell agents],” Raje said. “As we move these therapies earlier, we have to have that discussion with our patients. The good news is we haven’t seen anything new, and when a patient needs a CAR T-cell [therapy] I would not withhold it, even with the secondary cancer risk.”

At a median follow-up of 33.6 months (range, 0.1-45.0), patients who received cilta-cel (n = 208) experienced a significant OS benefit vs those in the SOC arm (n = 211; HR, 0.55; 95% CI, 0.39-0.79; 

 = .0009); study authors noted that cilta-cel was the first CAR T-cell agent to demonstrate an OS benefit in multiple myeloma. The 30-month OS rates were 76.4% and 63.8%, respectively. Cilta-cel also conferred a significant PFS benefit over SOC regimens (HR, 0.29; 95% CI, 0.22-0.39; 

 < .0001), with 30-month PFS rates of 59.4% and 25.7%, respectively.

“One of the things that we learned from CARTITUDE-4 is the importance of controlling disease prior to CAR T infusion,” Ajai Chari, MD, noted. “There’s an International Myeloma Working Group sequencing paper [in which] we’re proposing the term onboarding, which is what you do before you get to collection and then bridging would be what you do after collection.” 

Data from CARTITUDE-4 led to the April 2024 FDA approval of cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.15 The expanded indication made cilta-cel the only B-cell maturation antigen– directed therapy approved by the FDA in multiple myeloma as early as first relapse. 

“The very exciting news is we have these 2 [FDA]-approved CAR T products, ide-cel and cilta-cel, and this year we’ve had them both move up in the treatment paradigm,” Rossi said. “Instead of [them] being [available] in multiple- relapse [disease after] 4 prior lines, we have cilta-cel in [patients who received a] prior proteasome inhibitor and immunomodulatory agent [who are] refractory to lenalidomide and ide-cel for patients who’ve had 2 lines of therapy, including a proteasome inhibitor, immunomodulatory agent, and a CD38–[directed antibody]. [These are] slightly different indications, but [they’re helping us] work toward that plateau envy if we can get these effective therapies done earlier.”

FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed November 11, 2024. bit.ly/40HnRul 

Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA SC)/bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance in transplanteligible (TE) newly diagnosed myeloma (NDMM): PERSEUS cytogenetic risk analysis. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-48.

Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014. doi:10.1016/S1470-2045(24)00282-1

Corre J, Vincent L, Moreau, et al. Daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) and DARA maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM): CASSIOPEIA minimal residual disease (MRD) update. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-47.

Leypoldt L, Besemer B, Hanel M, et al. Isa-KRd in high-risk newly diagnosed multiple myeloma – 4-year-follow-up from the GMMG-CONCEPT trial. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-53.

Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomiblenalidomide- dexamethasone vs carfilzomib-lenalidomidedexamethasone as pre-transplant induction and posttransplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/ blood-2023-177546

Usmani SZ, Facon T, Hungria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-63.

Johnson & Johnson files for U.S. FDA approval of Darzalex Faspro-based quadruplet regimen for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 30, 2024. Accessed October 10, 2024. bit.ly/40NF99n

FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 29, 2021. Accessed November 11, 2024. bit.ly/3YMPcbS

FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. March 7, 2022. Accessed November 11, 2024. bit.ly/3Heb7jT

U.S. FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb. April 5, 2024. Accessed November 11, 2024. bit.ly/3UykBhC

Ailawadhi S, Arnulf B, Patel KK, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. Published online August 28, 2024. doi:10.1182/blood.2024024582

Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 21st International Myeloma Society Annual Meeting; September 25- 28, 2024; Rio De Janeiro, Brazil. Abstract OA-65.

Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 6, 2024. Accessed November 11, 2024. bit.ly/44aJDXa

Peer Exchange

Experts break down emerging data for the use of quadruplet regimens in newly diagnosed multiple myeloma.

Quadruplet Regimens Stand Strong in Newly Diagnosed Multiple Myeloma

An inclusive road map for change laid out in the 

 Breast Cancer Commission report, walking through 6 themes to address challenges in the field, marks an important step toward eradicating existing equity gaps.

The evidence-based plan, grounded in raising awareness for the many individuals living with metastatic breast cancer who have gone unaccounted for, was designed for all who are connected to breast cancer, but directed at policy makers. The report includes indicators of progress and highlights inequities in prevention, detection, treatment, and supportive care through its 6 pillars: prevent, personalize, include, collaborate, identify, and communicate (Figure).

“Some of the most exciting developments of 2024 came from the 

 Breast Cancer Commission,” Reshma Jagsi, MD, DPhil, coauthor of the report, said in an interview with 

. “The theme that I was most actively involved in was the theme [6] on patient empowerment and communication. We focused on trying to ensure that we support decisions with all the information that’s available and make sure that the wonderful research that’s being done in randomized trials gets to patients. [This is key] so that patients can reflect on the evidence and consider all the options that they have and make decisions that are concordant with their own values and preferences.”

In addition to emphasizing the importance of empowering patients by ensuring they are at the heart of clinical communication, another theme of the report focused on personalizing treatment.

The commission noted that health systems and clinicians should personalize care and that embracing digital technology in an equitable manner can reduce barriers, aid in connecting with patients who are hard to reach, and increase diversity and inclusion in clinical studies. Tying into the aforementioned themes is the theme of collaboration, which the report cited as key to closing the equity gap through global early diagnosis, treatment frameworks, and innovative technology.

“This commission brought together investigators from all over the globe who are continuing to collaborate and trying to build on this work to take the insights and the lessons that are in the report forward,” Jagsi said. “I [was] excited about opportunities to connect at the 2024 San Antonio Breast Cancer Symposium [SABCS] and the Miami Breast Cancer Conference

 and beyond with not only the collaborators on that report, but with the populations they represent.”

Discussions on the report’s findings at SABCS preceded those that will occur at the 

 Miami Breast Cancer Conference hosted by Physicians’ Education Resource

 Jagsi is serving as cochair of the multidisciplinary meeting in March 2025 in Florida.

“The chair of the report, Charlotte E. Coles, PhD, MRCP, FRCR, is going to be joining us as a speaker,” Jagsi noted. “And Felicia Knaul, PhD, a health economist and advocate will be delivering a keynote talk.”

A Call to Action for High-Quality Registry Data on Metastatic Disease

Breast cancer is now the most common cancer in the world and data revealed that at the end of 2020, 7.8 million women had been diagnosed with the disease in the past 5 years.

 However, it is unknown how many people are living with metastatic breast cancer because many cancer registries do not record data on relapses, which has created a large gap in knowledge.

 Breast Cancer Commission report was focused on groups [of patients] who have been ignored or forgotten, and another key theme was how patients with metastatic disease have not gotten the attention that they should have,” Jagsi explained. “We don’t even have accurate information on the prevalence of metastatic disease because registries don’t collect rigorous information on this.”

Therefore, the report called for high-quality data to be collected on cancer relapses worldwide and to identify patients with metastatic cancers in general, in addition to breast cancer. With this, the committee also suggested raising awareness and educating stakeholders/society to address the stigma around metastatic breast cancer and noted that the equitable implementation of global early detection, treatment frameworks, and innovative technologies via collaboration will aid in closing the equity gap in care and outcomes.

“With adequate resources and a shift in attitudes, it might be possible to cure some people, treat most, alleviate the suffering of all, and abandon no one,” the 

 Breast Cancer Commission wrote regarding patients with metastatic disease.

“That was a beautiful part of the report,” Jagsi noted, adding that, “We [also] use language in ways that sometimes is very unfortunate. We’ll talk about a patient having ‘failed,’ and of course the patient hasn’t failed—we have failed to control the disease in the patient.”

Changes in language and communication represent another needed next step to push the breast cancer field forward and elevate care for all.

Examining the Rising Incidence of Disease and Hidden Costs of Breast Cancer

Breast cancer incidence rates are expected to rise and countries with a low Human Development Index (HDI) are predicted to see a doubling of new diagnoses and deaths by 2040. Additionally, incidence and mortality rates are expected to increase by 70% and 60%, respectively, in countries with a medium HDI. By 2040, more than 3 million new diagnoses—an increase of 40% from 2020—and more than 1 million deaths—an increase of 50% from 2020—are anticipated per year.

“The incidence of breast cancer is now projected to reach more than 3 million [people] per year by 2040, and patients in low- and middle-income countries will be the hardest hit,” Jagsi said. “Prevention is essential, and there was also a focus on the hidden costs and suffering that are burdens that come with breast cancer [in the report as well], including the financial, physical, psychological, emotional, and social tolls of this disease.”

To address the hidden costs associated with breast cancer, the commission has called for the development of new, validated tools to record costs and suffering experienced by patients with breast cancer as well as their caregivers and families; the commission also asked for the development of metrics to measure the benefits that are placed on alleviating suffering related to breast cancer. They noted that the novel tools may influence policy makers to determine new priorities to ensure that there is financial protection, and that supportive and palliative care is available at every stage for patients with breast cancer. To calculate the true cost of breast cancer to societies and identify the costs, the report suggested more systematic monitoring of family income loss, cost-related nonadherence, treatment withdrawal, and quality of life. The report also emphasized that exposing and reducing costs could provide policy makers with an incentive to invest in prevention, early detection, cost-effective therapies, and the optimal management of breast cancer.

 Commission on Cancer and Health Systems, the 

 Breast Cancer Commission initiated a collaboration with partners in several countries to generate country-level, context-relevant costs and cost burden data to better inform priority setting on a health care system level for cancer control.” Additionally, it was highlighted that the Costs and Supportive Care in Breast Cancer study has conducted exploratory pilot research in the UK as the country has universal health coverage for cancer care via the National Health Service.

Furthermore, the report detailed how the advancements made in breast cancer beginning in the early 1990s have not been equal for all. Changes made regarding diagnoses and coordinated multidisciplinary evidence-based treatments have resulted in a decline in breast cancer mortality rates by approximately 2% each year, translating to a 40% reduction over more than 30 years in breast cancer age-standardized mortality rates. However, patients in low- and middle-income countries do not experience the same survival rates as others due to diagnoses being made when the disease is at an advanced stage and low diagnostic and treatment capacities. Data showed that 5-year breast cancer survival rates are greater than 90% in high-income countries whereas rates are 66% in India and 40% in South Africa. Approaches tailored to local communities that have worked well in high-income countries where fewer resources are available is a necessary next step to address this disparity, according to the report.

 Breast Cancer Commission outlined approaches for changes amongst each theme cited, key messages, risk factors, and more.

“This report was a tour de force, and it provides a road map of communication, inclusion, prevention, collaboration, and personalization,” Jagsi said. “It’s important to emphasize that this [report] is not a one-and-done endeavor—it is the foundation for so much collaborative work that we must push forward together.”

Coles CE, Earl H, Anderson BO, et al; Lancet Breast Cancer Commission. The 

. 2024;403(10439):1895-1950. doi:10.1016/S0140-6736(24)00747-5

The Lancet Commission on Breast Cancer publishes recommendations for change. Cancer Research UK. April 16, 2024. Accessed December 5, 2024. bit.ly/3ZDaxpP

 Breast Cancer Commission. Infographics. April 15, 2024. Accessed December 5, 2024. bit.ly/41lFLDh

 Miami Breast Cancer Conference. Physicians’ Education Resource, LLC. Accessed December 5, 2024. bit.ly/4iiv8qN

San Antonio Breast Cancer Symposium. Full program. Updated November 20, 2024. Accessed December 5, 2024. bit.ly/3ZqlWrV

The Lancet Breast Cancer Commission report outlines a comprehensive strategy to address equity gaps in breast cancer care through six themes: prevention, personalization, inclusion, collaboration, identification, and communication. It emphasizes patient empowerment, personalized treatment, and the need for high-quality data on metastatic disease. The report highlights the rising incidence of breast cancer, especially in low- and middle-income countries, and calls for tools to measure the hidden costs of the disease. It stresses the importance of global collaboration and tailored approaches to improve outcomes and reduce disparities.

Coauthor of the Lancet Breast Cancer Commission report, Reshma Jagsi, MD, DPhil, details the 6 themes of the evidence-based plan aimed to address challenges in the field.

A Road Map for Change Report Provides a Guide to Elevate Breast Cancer Care

The speed of our knowledge expansion regarding the molecular basis of cancer— which has transformed essentially all aspects of malignant disease management, from risk assessment and prevention to the role of tumor-agnostic antineoplastic drug delivery—has been nothing short of breathtaking.

It is sometimes difficult to remember that it was not that long ago when the only tool available to assign a potentially meaningful genetic risk of cancer was a detailed family history, assuming this information was available. Further, there were quite limited implications that such an assessment might favorably affect individual patient clinical outcomes, and there was even less utility for cancer prevention efforts for possibly affected relatives. Fortunately, this state of affairs has rather dramatically changed with the widespread availability of detailed germline and somatic tumor testing, which have become standard of care in multiple settings. 

Not surprisingly, along with these scientific and clinical developments come additional questions unique to this specific arena, some very practical and others quite conceptual in nature but still requiring at least an attempt to provide rational responses. 

For example, in the first category, the practical, one might directly ask, “How quickly is it necessary to obtain the results of genetic tests for an individual patient with cancer?” In the second category, the conceptual, it is reasonable to inquire why 

 mutations, recognized for their deleterious influence on the lifetime risks for the development of breast and ovary cancers, have from an evolutionary perspective persisted within the general population. 

What follows is an attempt by this commentator to provide brief responses to these provocative questions. 

Regarding the issue of testing timing, it is essential to divide the issue into several clinical scenarios based on the desired use of the molecular data.

The rapid advancement in understanding cancer's molecular basis has revolutionized its management, from risk assessment to treatment. Previously reliant on family history, genetic risk assessment now benefits from germline and somatic tumor testing. The timing of genetic testing varies based on clinical scenarios, with immediate results needed for therapeutic decisions and delayed testing acceptable for future treatment options or germline abnormalities. The persistence of BRCA mutations may be linked to evolutionary advantages, such as increased fertility, despite higher post-reproductive mortality, suggesting complex evolutionary dynamics in cancer genetics.

Maurie Markman, MD, delves into questions regarding precision medicine and genetic testing in cancer.

Vol. 26/No. 1 | Oncology Live®

AI-Enabled Chatbot Replicates Efficacy of SOC Approaches in Aiding Receipt of Cancer Genetic Testing

CLDN6-Directed Agents Generate Encouraging Early Activity in Solid Tumors

Quadruplet Regimens Stand Strong in Newly Diagnosed Multiple Myeloma

A Road Map for Change Report Provides a Guide to Elevate Breast Cancer Care

Unique Questions Associated With the Increasing Prominence of Precision/Genomic Medicine in Routine Cancer Care