Seeing the Whole Picture: Labs, Circulating Tumor DNA, Imaging, and Clinical Advocacy in the Management of Recurrent HR+ HER2- Breast Cancer

Background 

Invasive ductal carcinoma is the most common breast cancer subtype, and management requires careful coordination of surgery, systemic therapy, and close ongoing monitoring.¹  

Traditional follow-up often relies on imaging, lab work, and/or tumor markers, but these tools alone may not fully capture the complexity of a patient’s disease or response to treatment. Even when a patient follows a traditional treatment course for early-stage breast cancer and adheres fully to therapy—and despite low-risk features, such as low Ki-67—routine follow-up appointments remain imperative. New-age modalities, such as circulating tumor DNA (ctDNA) monitoring, advanced imaging, and genomic profiling provide additional insight, allowing clinicians to detect early shifts in tumor behavior, anticipate resistance, and personalize therapy, ensuring that even subtle or unexpected shifts in disease biology are not overlooked. 

Clinical Course 

A 40-year-old premenopausal woman was diagnosed with stage II (T2N1M0) left invasive ductal carcinoma, grade II, estrogen receptor (ER) Allred score 6, progesterone receptor (PR) Allred score 5, HER2 non-amplified (1+ IHC), and Ki-67 of 2%. Her initial hereditary genetic testing was negative. 

The patient received neoadjuvant chemotherapy with dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel, completing 10 out of 12 cycles. The regimen was abbreviated due to grade 2-3 neuropathy. She then underwent bilateral mastectomies with left sentinel lymph node biopsy, which revealed residual disease with 2/2 positive nodes (1 macrometastasis, 1 micrometastasis). Margins were clear, and the contralateral breast was free of malignancy. 

She underwent post-mastectomy radiation and adjuvant endocrine therapy with goserelin in combination with a nonsteroidal aromatase inhibitor, followed by a bilateral salpingo-oophorectomy (with subsequent discontinuation of goserelin). She was not a candidate for adjuvant abemaciclib. Following these treatments, she continued adjuvant letrozole daily for 4.5 years, with routine follow-up, including CA 15-3 monitoring. 

During a routine visit, her CA 15-3 level rose to 23.3 (baseline 9-10), raising concern and prompting further evaluation via a ctDNA test, which returned a positive result of 2.172%. Full-body imaging was then performed, revealing two new low-attenuation lesions in the liver (2.6 cm and 2.7 cm), which were suspicious for metastatic disease. An initial biopsy was inconclusive, necessitating a repeat biopsy, which ultimately confirmed recurrent metastatic breast cancer: ER Allred 7, PR Allred 0, HER2 non-amplified (1+). Molecular profiling of archived tissue revealed: GATA3 p.N332fs, ARID1A p.Q521fs, ABCC3 copy number gain, CDKN2A/B loss, FRS2, MDM2, PPM1D, RPS6KB1, YEATS4 gains, low tumor mutational burden (3.7), and MSI stable. 

During the work up (approximately 1 month later), the ctDNA tumor fraction increased to 7.678%, indicating a more aggressive phenotype. Given prior progression on endocrine therapy, she started fulvestrant 500 mg intramuscular monthly plus ribociclib 600 mg daily (21/7 schedule) per MONALEESA-3.³ Subsequent cycles were reduced to ribociclib 200 mg due to ongoing neutropenia. After 3 cycles, scans showed hepatic progression, and ctDNA tumor fraction exceeded 30%. 

A subsequent liquid biopsy identified: RB1 loss; MEG9-BRCA1 fusion; TSC1 S282*; ARID1A Q521Lfs100; FGFR1 and RAF1 amplifications ATM, BRCA2, STK11 single-copy losses; CDKN2A biallelic loss; GATA3 N332Efs21; TMB 4.75; MSI stable. No common endocrine resistance mutations (ESR1, PIK3CA, AKT1, or PTEN) were detected; therefore, none of the identified genomic alterations were considered actionable or expected to influence treatment selection. Given the clinical context, trastuzumab deruxtecan was initiated, prioritizing a more intensive treatment strategy.  

Differentiating Between Progressive Disease and Pseudoprogression 

The patient received 3 cycles of trastuzumab deruxtecan before follow-up staging scans (CT chest, abdomen, pelvis, and bone scan) were evaluated. The results showed new hypodensities in the liver and a larger infiltrative hepatic mass, raising concern for progressive disease. There was some consideration that these findings could represent pseudoprogression due to treatment responses.  

Her case was reviewed at a multidisciplinary tumor board, where the consensus favored progressive disease. However, additional imaging was obtained to better monitor the liver lesions. An abdominal/liver MRI was performed, given the differences in modality and contrast timing. A ctDNA liquid biopsy was also obtained to compare with previous scans and tumor fraction levels. This revealed a dramatic decrease in tumor fraction to 0.856%. 

The MRI initially suggested an increase in the size of hepatic metastases when compared with an MRI from 6 months prior. Because this earlier comparator scan predated her most recent treatment, the advanced nurse practitioner contacted the radiologist to provide additional clinical context and request comparison with more recent scans from 3 months earlier, despite differences in imaging modality. With this updated context, the radiologist revised his report and concluded that the imaging actually demonstrated treatment response. In combination with the significant decrease in ctDNA tumor fraction, it was determined that the patient was experiencing pseudoprogression, consistent with a treatment response. 

The patient continues trastuzumab deruxtecan, with an ongoing decrease in tumor fraction. Her most reported symptoms are chronic grade 2 fatigue, hair loss, and hot flashes. 

Discussion 

At the time of the patient's initial treatment, she was not a candidate for the adjuvant CDK4/6 inhibitor abemaciclib, and ribociclib had not yet been approved. For eligibility in the monarchE clinical trial, which supported abemaciclib’s approval, patients needed to have HR+ HER2-, node-positive, resected early-stage breast cancer with clinical and pathological features indicating a high risk of disease recurrence.⁴Specifically, high-risk features included either 4 or more positive axillary lymph nodes or 1-3 positive axillary lymph nodes along with at least one of the following: tumor grade 3, tumor size ≥ 50 mm, or a Ki-67 score ≥ 20%.² Ribociclib, which has since been approved as a CDK4/6 inhibitor for use in the early-stage adjuvant setting, was not approved until nearly 4 years after her initial diagnosis. 

In this case, the patient's liver lesions were initially reviewed by a multidisciplinary tumor board, where the consensus leaned toward progressive disease. Although this assessment is essential for determining the next steps, it is crucial to reflect the sequence of information gathering and decision-making. Ideally, the tumor board should have been provided with all relevant information prior to the meeting, particularly more comprehensive lab results and imaging studies. In this instance, an abdominal/liver MRI was performed after the tumor board meeting, instead of being available beforehand. Given the differences in modality and contrast timing between CT and MRI, the MRI could have provided more precise and potentially different insights into the status of the lesions. Furthermore, the ctDNA test, which was obtained after the tumor board's consensus, significantly contributed to the decision-making process. The ctDNA revealed a dramatic decrease in tumor fraction to 0.856%, suggesting a response to treatment that had not been fully captured in the initial imaging. This critical piece of information should ideally have been available prior to the tumor board meeting to provide a more complete and up-to-date understanding of the patient's clinical status. 

The AP’s Role  

Upon the patient’s presentation with an elevated CA 15-3 level, the AP listened attentively to the patient’s concerns. Although the value was within the normal range, the patient's anxiety over the rise in the tumor marker prompted the provider to take swift action. Recognizing the importance of early detection and the potential for subtle disease recurrence, the AP decided to investigate further by ordering additional testing, such as ctDNA and full-body scans, earlier than initially planned. In this proactive approach, informed by the patient's concerns and the clinical context, the AP initiated a timely investigation, which ultimately led to the identification of metastatic disease. By acting quickly, the AP demonstrated both clinical vigilance and a patient-centered approach to care.  

Building on this proactive approach, the AP’s ongoing involvement in the patient’s care ensured more accurate interpretation of diagnostic findings. In this case study, the AP acted as a clinical advocate by reaching out to the radiologist directly to provide additional clinical context regarding the patient’s history and recent treatment with trastuzumab deruxtecan. This communication ensured that the MRI results were interpreted correctly, reflecting treatment response rather than disease progression, preventing unnecessary changes to the treatment plan. The AP also integrated diagnostic data from ctDNA and imaging, identifying a significant decrease in tumor fraction, which suggested pseudoprogression rather than true disease progression. 

It was and is important to provide detailed explanations about the behind-the-scenes processes, including education on pseudoprogression and ctDNA. By doing so, the AP can help alleviate the patient’s concerns, fostering trust in the health care team. Throughout treatment, the AP should monitor and manage side effects from the patient’s treatment, proactively addressing these issues to maintain the patient’s comfort and quality of life. Finally, the AP should ensure continuous monitoring through regularly scheduled follow-up visits, labs, testing, imaging, and ctDNA assessments to track disease progression and adjust treatment, as needed, in close collaboration with the oncologist.  

Conclusion 

This case emphasizes the importance of viewing the patient comprehensively and integrating molecular and imaging data with the lived experience of treatment, side effects, and emotional well-being—including the patient’s own concerns, such as anxiety over a slightly elevated tumor marker, even when it remained within the normal range. It also highlights the critical role of the AP in ensuring a comprehensive understanding of the patient’s condition, including collaborating with the radiologist to re-evaluate imaging when additional clinical context may provide a more complete picture of the disease. Together, this demonstrates how a comprehensive, patient-centered approach can guide clinical decisions, particularly in the context of treatment resistance and apparent disease progression, while keeping the patient’s life, goals, and perspective central to care. 

References 

1. Invasive ductal carcinoma (IDC). Breastcancer.org. Accessed April 3, 2026. https://www.breastcancer.org/types/invasive-ductal-carcinoma 
2. Eli Lilly and Company. Verzenio (abemaciclib) [package insert]. Eli Lilly and Company 
3. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149.  
4. Johnston S, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomized, open-label, phase 3 trial. Lancet Oncol. 2022;24(1):77-90. doi: 10.1016/S1470-2045(22)00694-5.