Dr Mouabbi on the Rationale for Early, Serial ESR1 Mutation Testing in HR+ Breast Cancer  

] mutation early is critical. If patients are kept on AIs without switching therapies, the resistant clone can expand, potentially leading to disease progression… The mutation can emerge at any time, making it important to assess for 

mutations early and perform serial testing over the course of treatment."

Jason A. Mouabbi, MD, an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the importance of testing for 

 mutations prior to radiographic progression in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

 mutations represent a clinically significant mechanism of resistance in HR-positive, HER2-negative breast cancer, Mouabbi began. These mutations are classified as therapy-selected alterations, commonly arising in response to prolonged exposure to endocrine therapies, particularly aromatase inhibitors (AIs), which are widely used in the first-line metastatic setting, he stated.

 mutations result in a constitutively active estrogen receptor (ER), which no longer requires ligand binding for activation, he continued. Under healthy physiologic conditions, the ER remains inactive until bound by estrogen, at which point it promotes transcriptional activity leading to cell proliferation, Mouabbi detailed. However, in the presence of 

 mutations, the receptor remains in an active conformation independent of estrogen, according to Mouabbi. Consequently, AIs—which work by depleting estrogen—lose efficacy, allowing tumor proliferation to continue despite estrogen suppression, Mouabbi explained.

 mutations is critical for optimizing treatment sequencing, Mouabbi reiterated. Continued use of AIs in patients harboring 

 mutations may enable clonal expansion of resistant subpopulations, resulting in more aggressive disease that is less responsive to subsequent therapies, he said. Because 

 mutations can arise dynamically throughout treatment, serial testing, such as with circulating tumor DNA, is essential to identify the emergence of resistance and guide timely therapeutic adjustments, Mouabbi added.

 mutations are uncommon at the time of initial metastatic diagnosis among patients previously treated with endocrine therapy in the early-stage setting, he reported. However, this frequency increases with continued exposure to anti-estrogen therapies, reaching approximately 20% to 30% in the first-line metastatic setting and approximately 40% in later-line settings, Mouabbi noted. These data underscore the cumulative selection pressure imposed by endocrine agents and highlight the importance of molecular monitoring to inform precision treatment strategies in advanced HR-positive, HER2-negative breast cancer, Mouabbi concluded.

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Jason A. Mouabbi, MD, discusses how ESR1 mutations can cause patients with HR-positive, HER2-negative breast cancer to develop endocrine resistance.

Dr Mouabbi on the Rationale for Early, Serial ESR1 Mutation Testing in HR+ Breast Cancer

Dr Mouabbi on Challenges Diagnosing and Managing Invasive Lobular Carcinoma 

Jason A. Mouabbi, MD, assistant professor, Department of Breast Medical Oncology, Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses unique challenges associated with diagnosing and managing invasive lobular carcinoma.

Mouabbi states that for many years, the cancer research community at large failed to recognize the distinct nature of invasive lobular carcinoma. Instead, it often treated this disease similarly to invasive ductal carcinoma, which is the most common form of breast cancer.

One ongoing diagnostic challenge is the limitations of conventional breast imaging techniques, such as mammography, Mouabbi continues. Although these modalities are highly effective at detecting invasive ductal carcinoma, they are less effective when identifying invasive lobular carcinoma, Mouabbi explains. This often leads to later-stage diagnoses for patients with invasive lobular carcinoma. Consequently, invasive lobular carcinoma tends to be diagnosed at a more advanced stage, which negatively impacts overall outcomes, he says.

The delayed diagnosis and subsequent treatment challenges associated with invasive lobular carcinoma are reflected in the long-term prognosis of patients, Mouabbi reports. He adds that the 10-, 15-, and 20-year survival rates for patients with invasive lobular carcinoma are generally inferior to those for patients with invasive ductal carcinoma.

The higher rate of late disease recurrence observed in this patient population underscores the need for ongoing vigilance and long-term follow-up, Mouabbi says. Although many patients diagnosed with early-stage invasive lobular carcinoma can have a good prognosis following initial treatment, the cumulative risk of late recurrence necessitates sustained monitoring and potential interventions to mitigate this risk over time, he emphasizes.

Mouabbi concludes that future research focused on advancements in imaging techniques could facilitate earlier detection of invasive lobular carcinoma. He stresses the importance of recognizing the distinct nature of invasive lobular carcinoma in clinical practice and research, which could lead to the development of more effective diagnostic tools and treatment approaches tailored specifically to this subtype of breast cancer. With multiple ongoing trials within this space, Mouabbi expresses hope that the long-term prognosis for patients with invasive lobular carcinoma can be improved.

Jason A. Mouabbi, MD, discusses challenges associated with diagnosing and managing invasive lobular carcinoma

Dr Mouabbi on Clinical Trials for Invasive Lobular Breast Cancer

Jason A. Mouabbi, MD, assistant professor, Department of Breast Medical Oncology, Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses upcoming clinical trials aimed at expanding the treatment paradigm for patients with invasive lobular breast cancer.

Mouabbi highlights 3 notable studies currently running in this space. First, the phase 2 REPLOT trial (NCT06408168)is investigating the ROS1 inhibitor repotrectinib (Augtyro) with or without fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative metastatic invasive lobular carcinoma whose disease progressed following first-line therapy endocrine therapy that included a CDK 4/6 inhibitor. Mouabbi explains that this is the first clinical trial in the United States evaluating a ROS1 inhibitor such as repotrectinib in this setting, and he adds that enrollment is expected to initiate soon.

Another phase 2 study (NCT05919108) will investigate neoadjuvant neratinib (Neralynx) in combination with endocrine therapy for patients with stage I to III invasive lobular breast cancer harboring 

 mutations. HER2 mutations are more common in patients with invasive lobular breast cancer, Mouabbi explains, noting that these appear in approximately 15% of patients compared with approximately about 5% of patients with ductal cancers. This trial aims to assess whether targeting 

 mutations could provide a beneficial therapeutic approach for patients with lobular breast cancer, he says.

A third upcoming study called NeoAKT will investigate the neoadjuvant combination of capivasertib (Truqap) and letrozole in postmenopausal patients with stage II to III, estrogen receptor–positive, HER2-negative invasive lobular carcinoma. The study will enroll patients irrespective of mutation status, according to Mouabbi, as the trial seeks to include patients with early-stage lobular breast cancer to examine the potential of AKT inhibition in this patient population.

Mouabbi explains that in each of these studies could represent a critical step forward in addressing the unique characteristics of lobular breast cancer. Through exploring the use of more targeted therapies and combinations, these trials aim to enhance treatment efficacy and expand the options available for patients with this distinct form of breast cancer, he concludes.

Jason A. Mouabbi, MD, discusses clinical trials aimed at expanding the treatment paradigm for invasive lobular breast cancer.

Dr Mouabbi on the Use of Ribociclib vs Abemaciclib in HR+/HER2– Breast Cancer

Jason Abdou Mouabbi, MD, assistant professor, Department of Breast Medical Oncology, Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses considerations for the use of ribociclib (Kisqali) vs abemaciclib (Verzenio) in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

The phase 3 NATALEE trial (NCT03701334) evaluated adjuvant ribociclib in patients with HR-positive, HER2-negative early breast cancer. The phase 3 monarchE trial (NCT03155997) investigated adjuvant abemaciclib plus endocrine therapy in this patient population.

The definitions of high-risk HR-positive, HER2-negative metastatic breast cancer differed between the monarchE and NATALEE trials, Mouabbi says. monarchE only enrolled patients with lymph node–positive disease, whereas NATALEE included patients with either lymph node–positive or –negative disease. Therefore, based on these trial populations, a broader range of patients with HR-positive, HER2-negative breast cancer qualifies for ribociclib than abemaciclib, Mouabbi notes.

Although cross-trial comparisons are generally not advisable, informally comparing the findings from these 2 studies may provide useful insights in the absence of head-to-head comparisons between ribociclib and abemaciclib in this setting, Mouabbi cautions. monarchE included a higher proportion of patients with disease involvement in 4 or more lymph nodes than NATALEE. Consequently, some breast cancer experts may advise the use of abemaciclib for the highest-risk patients with extensive lymph node involvement and the use of ribociclib for those with lode-negative or lower-risk disease, Mouabbi explains. However, treatment decisions based solely on these criteria are not straightforward, Mouabbi emphasizes.

The administration schedules and adverse effect (AE) profiles also differ between these 2 agents, providing further evidence that specific patients may benefit more from 1 drug over the other, according to Mouabbi. Abemaciclib is taken twice daily continuously, whereas ribociclib is taken once daily for 3 weeks followed by a 1-week break every cycle. Additionally, the treatment durations differ for each regimen. In NATALEE, ribociclib was administered for 3 years, whereas in monarchE, abemaciclib was administered for 2 years.

Patient involvement in the treatment decision-making process is crucial, Mouabbi emphasizes. Some patients may prefer 1 drug to the other because of its administration schedule, AE profile, or treatment duration, Mouabbi says. Other patients may only qualify for 1 of these agents based on the enrollment criteria of the 2 studies, Mouabbi adds. Ultimately, detailed discussions with patients are crucial, as patients should have a significant say in their treatment plan, Mouabbi concludes.

Jason Abdou Mouabbi, MD, discusses considerations for the use of ribociclib vs abemaciclib in patients with HR-positive, HER2-negative breast cancer.

Jason Abdou Mouabbi, MD

Articles

Dr Mouabbi on the Rationale for Early, Serial ESR1 Mutation Testing in HR+ Breast Cancer

Dr Mouabbi on Challenges Diagnosing and Managing Invasive Lobular Carcinoma

Dr Mouabbi on Clinical Trials for Invasive Lobular Breast Cancer

Dr Mouabbi on the Use of Ribociclib vs Abemaciclib in HR+/HER2– Breast Cancer