Medical Case: A persistent pain, and a delayed question

A 54-year-old woman has back pain and a long-neglected breast lump. Her clinical journey will require more than a single decision, challenging the tumor board to choose the right steps at the right time.

Initial Presentation

Maria S., 54 years old, post-menopausal, presents to her general practitioner after three months of persistent upper-back pain and progressive fatigue. She denies trauma, respiratory symptoms or fever, but reports nocturnal pain partially relieved by NSAIDs. When questioned more thoroughly, she also admits noticing a lump in her right breast six to eight months earlier, which she dismissed out of embarrassment and fear.

Her medical history is unremarkable: no prior breast disease, no known BRCA mutations, no hormonal replacement therapy, no relevant comorbidities. She has no first-degree relatives with breast or ovarian cancer. She does not smoke and drinks alcohol occasionally.

On physical examination, inspection of the right breast reveals mild skin retraction in the upper-outer quadrant. Palpation identifies a firm, irregular 2,5 cm nodule, poorly mobile from surrounding tissue, and a 1,5 cm ipsilateral axillary lymph node. No nipple discharge is present. Cardiorespiratory exam is normal. Palpation of the thoracic spine elicits focal tenderness over T7-T8. ECOG Performance Status: 0.

Given the palpable mass and the suspicious clinical features, Maria is referred to a dedicated breast clinic for diagnostic work-up, including imaging and tissue sampling.

Diagnostic work-up

Maria is managed in an outpatient breast clinic after referral from her GP. Within a few days of the initial visit, she undergoes bilateral mammography and targeted breast ultrasound, which confirm a suspicious picture: a 24-26 mm spiculated lesion in the upper-outer quadrant of the right breast with architectural distortion, and an enlarged level-I axillary lymph node showing cortical thickening and loss of fatty hilum. The radiologist classifies the findings as BI-RADS 5, strongly suggestive of malignancy. Because imaging and clinical exam are concordant, the team proceeds without delays to tissue sampling.

Two days later, an ultrasound-guided core needle biopsy of the breast lesion is performed (three cores), along with a fine-needle aspiration of the axillary node. Maria remains anxious but clinically stable during this period; she continues to live at home, requires only NSAIDs for back pain, and shows no signs of urgent complications. She is not hospitalized.

The pathology report arrives ten days after her first clinic evaluation, confirming invasive ductal carcinoma, grade 2. Immunohistochemistry reveals a luminal-like profile (ER 90%, PR 10%), with HER2 IHC 1+ (HER2-low by current standards) and Ki-67 of 25%. Cytology from the axillary node is positive for metastatic carcinoma, indicating at least clinical N1 disease.

Because of Maria’s persistent and localized thoracic pain, the case is presented at the multidisciplinary tumor board(MDT) the same week. The panel agrees that local surgery would be premature and that the priority is to complete staging to evaluate possible systemic spread. A contrast-enhanced CT of the chest, abdomen and pelvis, followed by a bone scan, is arranged urgently. The scans reveal multiple osteoblastic lesions in the thoracic spine (T7–T8) and the iliac crest, as well as two subcentimeter hypodense liver nodules considered suspicious for metastasis. No lung disease is detected. Laboratory results show mildly elevated CA-15.3 with otherwise normal liver and renal function. Maria maintains an ECOG Performance Status of 0, and her pain remains manageable as an outpatient.

At this point, roughly three weeks after her first medical contact, the diagnostic picture is complete: HR-positive/HER2-low metastatic breast cancer, predominantly bone-involving, with early visceral deposits in the liver. The MDT confirms that she will continue to be managed as an outpatient, and plans both systemic treatment and bone-targeted therapy, pending dental evaluation.

Start endocrine therapy plus a CDK4/6 inhibitor and plan antiresorptive therapy

At this stage, the priority is to control a systemic disease with a systemic treatment. Maria has HR-positive, HER2-low metastatic breast cancer, bone-predominant and without signs of visceral crisis. She is symptomatic but stable, with a good performance status and no immediate threat to organ function. For this type of presentation, all major guidelines support endocrine therapy combined with a CDK4/6 inhibitor as the most effective first-line option. This strategy offers the best chance of prolonging disease control with manageable toxicity, while antiresorptive therapy is indicated to prevent skeletal complications.

Surgery is not the right first move: removing the breast would not change the natural history of a disease that is already systemic, and there is no evidence of a survival benefit in this context. Radiotherapy may become useful later for focal pain or structural complications, but it cannot replace a systemic approach. Repeating the biopsy to search for HER2 amplification would not alter the therapeutic plan, since the tumor clearly shows a HER2-low profile and there is no indication for ISH confirmation.

First-Line treatment and clinical course

Maria begins endocrine therapy combined with a CDK4/6 inhibitor as an outpatient, after a thorough discussion with the breast unit team about treatment goals, expected benefits and potential side effects. During the first months, she experiences a progressive reduction in back pain and a gradual return to normal activity, with only mild fatigue and transient neutropenia. She undergoes regular monitoring, including blood tests every two weeks during the initial cycles, followed by monthly assessments and imaging every three to four months. The addition of an antiresorptive agent is scheduled shortly after dental clearance, and she tolerates it without significant complications. Her ECOG remains 0-1.

For more than a year, the disease stays under control. However, at approximately month fourteen, Maria reports a return of nocturnal back pain and new, intermittent discomfort in her right flank. Restaging shows a mixed picture: some bone lesions remain stable, but others have progressed, and two small liver nodules have become more conspicuous. There is no visceral crisis, but the disease is clearly escaping endocrine blockade. HER2 status remains unchanged (IHC 1+), confirming a HER2-low metastatic profile, and her performance status remains acceptable for further therapy.

The MDT meets again. With progression after endocrine treatment plus CDK4/6 inhibition, the team evaluates the best second-line approach.

Start trastuzumab-deruxtecan

At this stage, the disease is progressing under endocrine blockade, and simply switching to another endocrine agent would offer limited benefit. Chemotherapy remains an option, but current evidence has reshaped the second-line landscape for HER2-low metastatic disease: trastuzumab-deruxtecan has emerged as the treatment capable of significantly improving disease control and survival, compared to standard chemotherapy, with a manageable safety profile when monitored properly. For Maria, still in good clinical condition and without visceral crisis, this represents the most appropriate next step.

Second-line treatment and early benefit, then a new problem

Maria begins trastuzumab-deruxtecan as second-line therapy. Before treatment initiation, she undergoes baseline pulmonary assessment, including HR-CT and pulse oximetry, both normal. She is informed about the risk of drug-related interstitial lung disease (ILD) and instructed to promptly report respiratory symptoms. The first cycles are well tolerated; apart from mild nausea and alopecia, she maintains a good quality of life, continues to work part-time, and remains physically active.

At the eight-week restaging, CT shows a partial radiological response, with reduction of liver nodules and decreased metabolism in the spine on PET/CT. Maria feels encouraged for the first time since diagnosis. Her ECOG remains 1.

Around week sixteen, however, she reports a new dry cough and mild exertional dyspnea, without fever or infections in household contacts. On examination, oxygen saturation is slightly reduced compared to baseline (95% vs 98% at rest) and fine bibasilar crackles are audible. C-reactive protein is normal; there is no leukocytosis. A prompt HR-CT is performed, revealing diffuse bilateral ground-glass opacities without consolidation or pleural effusion, radiologic findings that raise suspicion for treatment-related ILD. The MDT is reconvened urgently, with pulmonology involved.

Maria is worried. She is experiencing her first significant toxicity since diagnosis, at a moment when the tumor was finally responding. The team must make a clear and timely decision.

Hold T-DXd and start corticosteroids

Because this presentation is consistent with suspected Grade ≥2 ILD, the priority is to immediately stop T-DXd and start systemic corticosteroids, even before definitive exclusion of infection. Delaying intervention markedly increases the risk of irreversible lung damage. Antibiotics have no role unless infection is likely, and continuing T-DXd in the presence of pulmonary toxicity is unsafe. Switching to chemotherapy now would address the tumor but not the lung toxicity, and would ignore the urgent need for steroid treatment. The correct sequence is: interrupt, diagnose, treat inflammation, re-stage, then re-plan systemic therapy.

After ILD: a turning point in the therapeutic journey

Maria starts high-dose prednisone under close monitoring. Over the following 10–14 days, her cough improves and dyspnea gradually resolves. A repeat HR-CT shows partial radiological regression of the ground-glass infiltrates. With respiratory stability recovered, the tumor board reconvenes.

At this stage, the team faces a difficult reality: although T-DXd was effective on the tumor, re-exposure is not recommended after a suspected Grade ≥2 ILD. The therapeutic question becomes how to maintain systemic control without jeopardizing lung safety.

Maria, now emotionally more fragile and afraid of losing the progress she made, expresses concern that “everything is starting again.” The team validates her fears and explains the next step clearly: the goal remains disease control, but with a safer agent.

Switch to single-agent chemotherapy

Re-exposure to T-DXd is contraindicated after Grade ≥2 ILD because recurrence can be rapid and life-threatening. Endocrine monotherapy would likely be ineffective in a progressing, endocrine-resistant tumor. Observation is inappropriate in an active metastatic disease. In this setting, sequential chemotherapy is the right balance between efficacy and safety, in line with contemporary treatment algorithms.