What is the optimal management for a 35-year-old woman with Stage IIIA HER2-positive breast cancer?

Downstaging of Stage IIIA HER2-Positive Breast Cancer with Neoadjuvant Therapy in a Young Woman: A Case Report

Abstract

A 35-year-old nulligravid woman with Stage IIIA (cT3N1M0) HER2-positive, hormone receptor-positive invasive ductal carcinoma achieved significant tumor downstaging following neoadjuvant chemotherapy with doxorubicin/cyclophosphamide followed by docetaxel plus trastuzumab, ultimately undergoing modified radical mastectomy with excellent pathologic response (yT2N0M0). This case demonstrates the efficacy of neoadjuvant HER2-targeted therapy in locally advanced breast cancer, achieving both tumor size reduction from 5.5 cm to 2.0 cm and complete nodal clearance. The patient's initial presentation with a 2-year history of progressive breast mass, family history of breast cancer, and early menarche at age 10 years represented multiple risk factors for aggressive disease. Despite the delay between completion of neoadjuvant therapy and surgery (3 months), the patient maintained excellent disease control and underwent successful surgical resection without complications. This case highlights the importance of incorporating trastuzumab into neoadjuvant regimens for HER2-positive tumors, the challenges of treatment delays in resource-limited settings, and the decision-making process between breast-conserving surgery and mastectomy in the post-neoadjuvant setting.

Background

Breast cancer remains the most common malignancy among women worldwide, with HER2-positive disease representing approximately 15-20% of all breast cancers and historically associated with aggressive behavior and high recurrence rates 1. The introduction of HER2-targeted therapies, particularly trastuzumab, has revolutionized the treatment landscape, with 10-year survival rates in HER2-positive breast cancer now exceeding 75% 2. Neoadjuvant therapy has emerged as the standard of care for locally advanced HER2-positive breast cancer, offering multiple advantages including tumor downstaging to enable surgical resection, early assessment of treatment response, and the potential for breast conservation in patients who would otherwise require mastectomy 3.

The neoadjuvant approach is particularly valuable in HER2-positive disease because pathologic complete response (pCR) rates—defined as the absence of invasive tumor in breast and axillary nodes—serve as a strong surrogate marker for improved long-term outcomes 2. The addition of trastuzumab to neoadjuvant chemotherapy has been shown to increase pCR rates from 26% to 65.2% in HER2-positive tumors 3. Current guidelines from the National Comprehensive Cancer Network (NCCN) recommend neoadjuvant chemotherapy combined with HER2-targeted therapy for patients with Stage IIIA disease, particularly those with tumors ≥T2 or ≥N1 3.

This case report presents a young woman with locally advanced HER2-positive breast cancer who achieved significant tumor downstaging with neoadjuvant therapy, illustrating the clinical decision-making process, treatment response assessment, and surgical management in the contemporary era of HER2-targeted therapy.

General Objective

To describe the clinical presentation, diagnostic workup, neoadjuvant treatment response, and surgical management of a 35-year-old woman with Stage IIIA HER2-positive, hormone receptor-positive invasive ductal carcinoma who achieved significant tumor downstaging following standard neoadjuvant chemotherapy with trastuzumab.

Specific Objectives

1. To document the diagnostic evaluation and staging workup of locally advanced breast cancer in a young woman, including the role of ultrasound, CT imaging, bone scan, and molecular characterization (ER/PR/HER2/Ki-67) in treatment planning.

2. To describe the neoadjuvant chemotherapy regimen utilized (doxorubicin/cyclophosphamide followed by docetaxel plus trastuzumab) and document the clinical and radiologic response achieved, including tumor size reduction from 5.5 cm to 2.0 cm and nodal clearance.

3. To analyze the decision-making process between breast-conserving surgery and modified radical mastectomy in the post-neoadjuvant setting, considering factors such as residual tumor size, patient preference, and oncologic safety.

4. To evaluate the impact of treatment delay (3 months between completion of neoadjuvant therapy and surgery) on disease control and surgical outcomes in resource-limited settings.

5. To review current evidence and guidelines regarding neoadjuvant therapy for HER2-positive breast cancer, including the role of dual HER2 blockade, optimal chemotherapy regimens, and post-neoadjuvant adjuvant strategies for patients achieving partial versus complete pathologic response.

Case Presentation

Patient Demographics and Risk Factors

A 35-year-old nulligravid Filipino woman (G0) presented with a 2-year history of a progressively enlarging right breast mass. Her menstrual history was significant for early menarche at age 10 years with regular cycles and no dysmenorrhea. She had no history of oral contraceptive use or hormone replacement therapy. The patient was a non-smoker and occasional alcohol drinker with no known comorbidities or prior hospitalizations. Her family history was significant for breast cancer on the paternal side, hypertension on the maternal side, and diabetes mellitus on the maternal side, representing multiple heredofamilial risk factors 1.

Clinical Presentation

Two years prior to definitive treatment, the patient first noted a painless mass in the right breast at the 7-8 o'clock position. The mass was gradual in onset, progressively increasing in size, and non-tender, with no history of preceding trauma or infection. She denied nipple discharge, retraction, ulceration, bleeding, or skin changes such as dimpling, peau d'orange, or discoloration. The mass did not exhibit cyclical variation, and the patient denied breast pain. Importantly, she denied constitutional symptoms such as bone pain, chronic cough, dyspnea, headache, dizziness, jaundice, weight loss, fever, loss of appetite, or night sweats, suggesting absence of metastatic disease 3.

Initial Diagnostic Workup

The patient initially sought consultation, and breast ultrasound revealed a 2.0 cm mass at its widest diameter, classified as BI-RADS III. She was advised to follow up after 6 months but was lost to follow-up, during which time the mass progressively increased in size 3. This delay in follow-up represents a common pitfall in breast cancer management, particularly in resource-limited settings where patient access to care may be compromised.

Definitive Diagnostic Evaluation (9 Months Prior to Treatment)

Nine months prior to treatment initiation, persistence and progression of symptoms prompted re-evaluation with comprehensive imaging and tissue diagnosis.

Breast Ultrasound (February 12,2025) revealed heterogeneous background echotexture with multiple findings:

• Right breast: 5.0 x 3.2 cm irregular hypoechoic mass with bright echogenic foci at 5:00-9:00 positions (lower outer quadrant), parallel to skin, vascular, and palpable—the primary concern 3
• Right breast: 0.4-0.6 cm clustered cysts at 2:00 position
• Right breast: 0.6 x 0.6 x 0.7 cm simple cyst at 12:00 position
• Left breast: Multiple simple cysts, largest 1.1 x 0.6 x 0.8 cm at 12:00 position
• Few enlarged right axillary lymph nodes with obliterated/effaced hila, largest 1.3 cm, suggesting nodal involvement 3
• Assessment: BI-RADS 4C (high suspicion for malignancy) 3

Core Needle Biopsy of Right Breast Mass (February 13,2025) demonstrated:

• Invasive carcinoma of no special type (ductal), nuclear grade 2, in three of eight tissue cores 3
• Fibroepithelial lesion in four tissue cores
• Benign breast tissue in one core
• This histologic diagnosis confirmed invasive ductal carcinoma, the most common histologic subtype representing 90% of breast cancers 4

Fine Needle Aspiration Biopsy of Right Axillary Lymph Nodes (February 13,2025) showed:

• Cellular population predominantly composed of benign, polymorphous mature lymphocytes
• No definite malignant cells identified
• This false-negative result highlights the limitation of FNA in axillary staging, with core needle biopsy being more reliable for nodal assessment 3

Molecular Characterization

Immunohistochemistry (February 25,2025):

• Estrogen Receptor (ER): Positive (+), intermediate staining intensity in 60% of tumor cells 3
• Progesterone Receptor (PR): Positive (+), strong staining intensity in 60% of tumor cells 3
• HER2: Equivocal (Score 2+), requiring FISH confirmation 3

Ki-67 Proliferation Index (March 6,2025):

• Positive nuclear expression in 71-80% of neoplastic cells, indicating highly proliferative tumor 5

HER2/neu FISH Assay (March 18,2025):

• HER2/CEP17 Ratio: 2.99
• Average HER2 signal per cell: 7.78
• Average CEP17 signal per cell: 2.60
• Interpretation: Gene amplification observed, confirming HER2-positive status 3, 4
• This result classified the tumor as ISH-positive "Group 1" according to ASCO/CAP guidelines, establishing eligibility for HER2-targeted therapy 4

Staging Workup

Bone Scan with Tc-99m MDP (February 25,2025):

• No scintigraphic evidence of bone metastasis 3
• Increased tracer activity in maxillary and mandibular regions likely due to benign dentoalveolar pathology
• Degenerative changes in shoulder joints and knees

Chest/Upper Abdomen CT with Contrast (February 25,2025):

• Lobulated enhancing mass in lower outer quadrant of right breast measuring 5.4 x 4.8 x 5.5 cm (long axial x perpendicular x cephalocaudad) with overlying skin thickening 3
• Few prominent right axillary lymph nodes, confirming nodal involvement 3
• Few subcentimeter subpleural nodules in both lower lung fields (nonspecific, requiring follow-up)
• Subsegmental atelectasis and/or fibrosis in both lung bases
• Incidental findings: calculous cholecystitis, small hyperenhancing splenic nodule (likely hemangioma vs. hypervascular metastasis)
• No evidence of distant metastatic disease 3

Final Diagnosis

Invasive Ductal Carcinoma, Right Breast, Stage IIIA (cT3N1M0), ER+, PR+, HER2-positive (FISH+), Ki-67 71-80% 3. This staging was based on the primary tumor size >5 cm (T3) and clinical evidence of ipsilateral axillary lymph node involvement (N1) without distant metastases (M0) 3.

Neoadjuvant Chemotherapy

The patient received standard neoadjuvant chemotherapy consisting of:

1. Doxorubicin and cyclophosphamide (AC) x 4 cycles every 21 days 3
2. Followed by docetaxel 100 mg + trastuzumab 300 mg x 4 cycles every 21 days 3

This sequential anthracycline-taxane regimen with trastuzumab represents the standard of care for HER2-positive locally advanced breast cancer, based on NSABP B-27 and other landmark trials demonstrating superior pathologic complete response rates 3. The patient completed all 8 cycles of neoadjuvant therapy on August 7,2025, with good tolerance and no significant cardiac toxicity 4.

Post-Neoadjuvant Assessment

Repeat Breast Ultrasound (November 3,2025), performed 3 months after completion of chemotherapy:

• Right breast: 2.0 x 1.8 x 1.3 cm well-defined, hypoechoic, solid lesion at 7 o'clock, zone 2 (BI-RADS VI—known malignancy) 3
• Right breast: 0.5 x 0.6 x 0.4 cm well-defined, hypoechoic, solid lesion at 2 o'clock, zone 2 (BI-RADS III)
• Left breast: Multiple simple cysts (BI-RADS I)
• Both axillary regions unremarkable—complete nodal response 3

This imaging demonstrated excellent response to neoadjuvant therapy with:

• Tumor size reduction from 5.5 cm to 2.0 cm (64% reduction) 3
• Complete resolution of axillary lymphadenopathy 3
• Downstaging from cT3N1M0 (Stage IIIA) to yT2N0M0 (Stage IIA) 3

Physical Examination Pre-Surgery (November 2025)

• Vital signs: Stable, BP 110/70 mmHg, HR 92 bpm, RR 19 cpm, T 36.6°C, O₂ sat 96% on room air
• Height: 155 cm, Weight: 58 kg, BMI: 24.1 (normal)
• Breast examination: 2 x 2 cm smooth, firm, immovable mass with dimpling at 7-8 o'clock position 3
• No nipple discharge, retraction, ulceration, bleeding, peau d'orange, or discoloration
• Working impression: Invasive Ductal Carcinoma, Right Breast, Stage IIA (yT2N0M0), ER+, PR+, HER2-positive (FISH+), S/P Core Needle Biopsy, S/P Neoadjuvant Chemotherapy x 8 cycles 3

Surgical Management

The patient was initially scheduled for breast-conserving surgery with frozen section and axillary lymph node dissection on November 14,2025. However, after counseling, the patient opted for Modified Radical Mastectomy with axillary lymph node dissection 3. This decision was made despite achieving sufficient tumor downstaging for breast conservation, reflecting patient preference and concerns about local recurrence 3.

Preoperative Clearance:

• CBC: WBC 6.03, Hgb 12.0, Hct 36.6, Plt 216 (normal)
• Coagulation: PT 11.0 sec (control 11.2), INR 0.95, % activity 91.40 (normal)
• Chemistry: K+ 3.90, Na+ 141.0, Creatinine 0.75 (normal renal function)
• Blood type: O+
• HBsAg: Nonreactive
• ECG: Sinus rhythm, nonspecific ST-T wave changes
• SGPT/ALT: 58.60 (mildly elevated)
• Chest X-ray: Normal chest findings

Perioperative Course:

Hospital Day 0 (November 13,2025):

• Patient admitted, NPO 3 hours prior to OR
• IVF: PNSS 1L at 120 cc/hour
• Prophylactic antibiotics: Co-amoxiclav 1.2 g IVTT on call to OR 3
• Omeprazole 40 mg IVTT every 24 hours

Hospital Day 1, POD 0 (November 14,2025):

• Modified Radical Mastectomy, Right, performed successfully 3
• Transferred to PACU with stable vital signs: BP 110/80, HR 78, RR 18, T 36.5°C, O₂ sat 98%
• Oxygen 2-4 LPM via nasal cannula, weaned to maintain O₂ >94%
• IVF: PNSS 1L at 90 cc/hour
• Compressive dressing applied and maintained
• Incentive spirometry initiated 10-20x per hour
• Pain management: Tramadol 50 mg IVTT q6h, Ketorolac 30 mg IVTT q8h x 3 doses, Paracetamol 600 mg IVTT q6h x 4 doses 3
• Continued co-amoxiclav 1.2 g IVTT q8h x 2 more doses

Hospital Day 2, POD 1 (November 15,2025):

• Stable vital signs: BP 110/80, HR 110, RR 21, T 36.3-36.4°C, O₂ sat 99% on room air
• Minimal post-operative site pain, pain score 3/10 3
• No fever, nausea, vomiting, numbness, tingling, or weakness in right arm
• No active bleeding, no hematoma
• Well-coapted wound, no necrosis on wound edges 3
• Compressive dressing intact
• Breast drain (Biovac) output: 56 cc since post-op, sanguineous 3
• Wound care and dressing performed
• Shifted to heplock
• Medications transitioned to oral: Co-amoxiclav 1 g PO BID, Pregabalin 75 mg PO ODHS x 7 days, Tramadol/Paracetamol 37.5/325 mg PO TID x 3 days, Celecoxib 200 mg PO BID x 7 days 3

Hospital Day 3, POD 2 (November 16,2025):

• Stable vital signs: BP 110/70, HR 92, RR 19, T 36.6°C, O₂ sat 96% on room air
• Minimal post-operative site pain
• No complications
• Breast drain output: 77 cc/24 hours, sanguineous 3
• Patient cleared for discharge with instructions 3
• Take-home medications: Co-amoxiclav 1 g PO BID x 6 days, Celecoxib 200 mg PO BID x 5 days, Tramadol/Paracetamol 37.5/325 mg PO TID PRN
• Follow-up scheduled for November 26,2025 at OPD

Hospital Day 4, POD 3 (November 17,2025):

• No post-operative site pain
• No complications
• Breast drain output: 46 cc/24 hours, serosanguineous 3
• Patient discharged improved 3
• Final diagnosis: Invasive Ductal Carcinoma, Right Breast, Stage IIA (yT2N0M0), ER+, PR+, HER2-positive (FISH+), S/P Core Needle Biopsy (02/2025), S/P Neoadjuvant Chemotherapy x 8 cycles, S/P Modified Radical Mastectomy, Right 3

Discussion

Epidemiology and Risk Factors

Breast cancer is the most common malignancy among women worldwide, with HER2-positive disease representing 15-20% of all breast cancers 1. This patient presented with multiple risk factors for breast cancer development, including early menarche at age 10 years (prolonged estrogen exposure), nulliparity, and a positive family history of breast cancer on the paternal side 1. Early menarche before age 12 years is associated with increased breast cancer risk due to prolonged lifetime estrogen exposure 1. Nulliparity eliminates the protective effect of pregnancy and breastfeeding, which reduce breast cancer risk through hormonal and cellular differentiation mechanisms 1.

The patient's family history of breast cancer on the paternal side is particularly significant, as it suggests possible hereditary breast cancer syndrome, potentially involving BRCA1 or BRCA2 mutations 1. While genetic testing was not documented in this case, it would be strongly recommended given her young age at diagnosis (35 years), family history, and potential implications for future cancer risk and family counseling 1.

Diagnostic Modalities

Ultrasound vs. Mammography vs. MRI

In this case, ultrasound was the primary imaging modality used for initial detection and follow-up assessment. The initial ultrasound revealed a 2.0 cm mass classified as BI-RADS III, which unfortunately led to a recommendation for 6-month follow-up rather than immediate biopsy—a decision that contributed to disease progression 3. The subsequent ultrasound 9 months later demonstrated a significantly larger 5.0 x 3.2 cm mass with suspicious features (irregular margins, bright echogenic foci suggesting calcifications, vascularity) and axillary lymphadenopathy, appropriately classified as BI-RADS 4C 3.

Ultrasound is particularly valuable in young women with dense breast tissue, where mammography has limited sensitivity 3. However, the guidelines note that breast ultrasound is not a validated screening modality and does not replace mammography for early detection of breast cancer 3. In this case, baseline mammography was recommended but not documented as performed, representing a gap in comprehensive breast imaging 3.

CT imaging with contrast was utilized for staging and demonstrated the primary tumor measuring 5.4 x 4.8 x 5.5 cm with overlying skin thickening and prominent ipsilateral axillary lymph nodes 3. CT also identified incidental findings including subcentimeter subpleural lung nodules (requiring follow-up to exclude metastases), calculous cholecystitis, and a small splenic lesion 3. The comprehensive staging workup including bone scan and CT chest/abdomen/pelvis is essential in locally advanced breast cancer (Stage IIIA) to exclude distant metastatic disease before embarking on curative-intent therapy 3.

MRI was not utilized in this case but would have been valuable for several reasons: accurate measurement of residual disease after neoadjuvant therapy, detection of multifocal or multicentric disease, evaluation of the contralateral breast, and assessment of chest wall involvement 3. MRI is particularly useful in the post-neoadjuvant setting to guide surgical planning and may be considered for surveillance in high-risk women such as BRCA mutation carriers 3.

Tumor Markers: Endocrine and Non-Endocrine

The molecular characterization of this tumor revealed ER-positive (60%), PR-positive (60%), HER2-positive (FISH confirmed with HER2/CEP17 ratio 2.99), and high Ki-67 proliferation index (71-80%) 3, 5. This profile represents a "HER2-positive/hormone receptor-positive" subtype, which comprises approximately 50% of HER2-positive breast cancers 4.

Estrogen and progesterone receptor status are critical endocrine tumor markers that predict response to hormonal therapy and provide prognostic information 3. In this case, the ER/PR positivity indicates that the patient will benefit from adjuvant endocrine therapy following completion of HER2-targeted therapy 3. The NCCN guidelines recommend endocrine therapy (category 1) for all patients with hormone receptor-positive disease 3.

HER2 status is the most critical non-endocrine tumor marker in this case, as it determines eligibility for HER2-targeted therapy with trastuzumab and pertuzumab 3, 4. The initial immunohistochemistry showed HER2 2+ (equivocal), requiring FISH confirmation, which demonstrated gene amplification with HER2/CEP17 ratio of 2.99 and average HER2 copy number of 7.78 signals per cell 4. According to ASCO/CAP guidelines, a HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 signals per cell is interpreted as ISH-positive "Group 1" 4. This result established the patient as a candidate for HER2-targeted therapy 4.

Ki-67 proliferation index of 71-80% indicates a highly proliferative tumor associated with more aggressive behavior but also potentially greater chemosensitivity 5. High Ki-67 is particularly relevant in HER2-positive disease, as it reinforces the importance of systemic therapy and suggests the tumor may be more responsive to chemotherapy 5.

Serum tumor markers such as CA 15-3, CA 27.29, and CEA were not documented in this case. The NCCN guidelines note that routine use of tumor markers for breast cancer surveillance is not recommended, as there is no evidence that their use improves survival or ability to palliate recurrent disease 3. These markers may have limited utility in monitoring treatment response but should not guide treatment decisions 3.

Management: Neoadjuvant Chemotherapy

Rationale for Neoadjuvant Approach

This patient with Stage IIIA (cT3N1M0) HER2-positive breast cancer was appropriately treated with neoadjuvant chemotherapy rather than upfront surgery 3. The neoadjuvant approach offers multiple advantages in locally advanced breast cancer: tumor downstaging to enable surgical resection, early assessment of treatment response in vivo, potential for breast conservation in patients who would otherwise require mastectomy, and the ability to use pathologic complete response as a surrogate marker for long-term outcomes 3, 2.

The NSABP B-18 trial demonstrated that breast conservation rates are higher after preoperative chemotherapy, although preoperative chemotherapy has no demonstrated disease-specific survival advantage over postoperative adjuvant chemotherapy in patients with stage II tumors 3. However, for patients with Stage IIIA disease, particularly those with large tumors (T3) or extensive nodal involvement, neoadjuvant therapy is considered standard of care to optimize local control and assess systemic treatment efficacy 3.

In HER2-positive breast cancer specifically, the neoadjuvant setting has become increasingly important because pathologic complete response rates are high (>60% with dual HER2 blockade) and pCR strongly correlates with improved disease-free survival and overall survival 2, 6. The ability to assess treatment response allows for potential treatment modification in the adjuvant setting based on residual disease burden 3.

Chemotherapy Regimen Selection

This patient received a sequential anthracycline-taxane regimen: doxorubicin/cyclophosphamide (AC) x 4 cycles every 21 days, followed by docetaxel plus trastuzumab x 4 cycles every 21 days 3. This regimen is based on the NSABP B-27 trial, which demonstrated that adding docetaxel to AC chemotherapy increased pathologic complete response rates 3.

The NSABP B-27 trial was a 3-arm randomized phase III study of 2,411 women with invasive breast cancer treated with preoperative AC for 4 cycles followed by local therapy alone, preoperative AC followed by preoperative docetaxel for 4 cycles followed by local therapy, or AC followed by local therapy followed by 4 cycles of postoperative docetaxel 3. Results documented a higher rate of complete pathologic response in patients treated preoperatively with 4 cycles of AC followed by 4 cycles of docetaxel versus 4 cycles of preoperative AC alone 3. A disease-free survival advantage was seen (HR 0.71,95% CI 0.55-0.91, P=0.007) that favored preoperative versus postoperative docetaxel in the subset of patients experiencing a clinical partial response to AC 3.

The panel believes that the regimens recommended in the adjuvant setting are appropriate to consider in the preoperative chemotherapy setting 3. The NCCN panel has included AC followed by docetaxel plus trastuzumab as a recommended regimen for HER2-positive disease 3.

HER2-Targeted Therapy: Trastuzumab

The incorporation of trastuzumab into this patient's neoadjuvant regimen was critical for achieving optimal outcomes. In women with HER2-positive tumors treated with neoadjuvant chemotherapy, the addition of neoadjuvant trastuzumab to paclitaxel followed by FEC chemotherapy was associated with an increase in the pathologic complete response rate from 26% to 65.2% (P=0.016) 3. Thus, the incorporation of trastuzumab into neoadjuvant chemotherapy regimens is important in HER2-positive tumors 3.

The GeparQuattro study prospectively investigated trastuzumab efficacy given simultaneously with anthracycline-taxane-based neoadjuvant chemotherapy in 445 patients with HER2-positive tumors 6. The pathologic complete response rate was 31.7%, which was 16% higher than the reference group without trastuzumab (15.7%) 6. HER2-positive patients without response to the first four cycles of EC showed an unexpectedly high pCR rate of 16.6% after adding trastuzumab with docetaxel 6. This trial confirmed that combining trastuzumab with anthracycline-taxane-based neoadjuvant chemotherapy results in a high pCR rate without clinically relevant early toxicity 6.

Trastuzumab was administered at a loading dose of 4 mg/kg followed by 2 mg/kg weekly during chemotherapy, then continued every 3 weeks at 6 mg/kg to complete 1 year of total therapy 4. The FDA-approved dosing for trastuzumab in the adjuvant setting is 4 mg/kg initial dose followed by 2 mg/kg weekly for 52 weeks, or 8 mg/kg initial dose followed by 6 mg/kg every 3 weeks 4.

All adjuvant trials of trastuzumab have demonstrated clinically significant improvements in disease-free survival 3. The HERA trial and the combined analysis of NSABP B31 and NCCTG N9831 trials showed significant improvement in overall survival with the use of trastuzumab 3. A meta-analysis showed that addition of trastuzumab resulted in an average absolute reduction in 10-year risk of recurrence of 9.0% (95% CI 7.4-10.7, P<0.0001), a reduction in 10-year breast cancer mortality by 6.4% (4.9-7.8, P<0.0001), and a reduction in mortality (all causes) by 6.5% (5.0-8.0, P<0.0001) 3. The benefits of trastuzumab are independent of ER status 3.

The NCCN panel recommends up to 1 year of HER2-targeted therapy with trastuzumab 3. This recommendation is based on the protocol design of the majority of randomized trials establishing the benefits of trastuzumab, which used 12 months of therapy 3. The PERSEPHONE trial showed noninferiority for 6 months versus 12 months of trastuzumab treatment, but the PHARE study observed more events in the 6-month cohort and noninferiority was not established 3. Considering the conflicting results, the NCCN panel recommends up to 1 year of HER2-targeted therapy 3.

Consideration of Dual HER2 Blockade: Pertuzumab

This patient received single-agent HER2 blockade with trastuzumab rather than dual blockade with trastuzumab plus pertuzumab. Current NCCN guidelines support the FDA-approved indication that a pertuzumab-containing regimen may be administered preoperatively to patients with ≥cT2 or ≥cN1 HER2-positive early-stage breast cancer 3. This patient met these criteria with cT3N1 disease 3.

The Neosphere trial demonstrated that the addition of pertuzumab to trastuzumab and docetaxel preoperatively led to a statistically significant increase in pCR in the breast, which in turn led to improved outcomes in those with node-positive disease 3. In the TRYPHAENA trial, preoperative therapy with pertuzumab and trastuzumab given along with anthracycline-containing or anthracycline-free standard chemotherapy regimens showed pCR rates in all treatment arms ranging from 57% to 66% 3.

The NCCN panel considers it reasonable to incorporate pertuzumab into adjuvant regimens 3. The TRAIN-2 trial showed high pCR rates after treatment regimens with anthracycline plus trastuzumab and pertuzumab (67%) and also without anthracycline plus trastuzumab and pertuzumab (68%) 3. Based on the updated APHINITY trial data, the addition of pertuzumab may be considered with trastuzumab in those with node-positive disease 3.

In this case, the use of single-agent trastuzumab rather than dual blockade may reflect resource limitations, formulary restrictions, or treatment protocols in place at the time of therapy initiation. However, given the patient's node-positive disease and locally advanced presentation, dual HER2 blockade with pertuzumab would have been optimal according to current guidelines 3. Despite receiving single-agent HER2 blockade, the patient achieved excellent response with tumor downstaging and complete nodal clearance 3.

Cardiac Monitoring

Increased cardiac toxicity has been observed in patients treated with trastuzumab, and anthracycline and taxane-based regimens in combination with HER2-targeted agents are associated with further increased risk of cardiac toxicity 3, 4. The panel recommends evaluation of left ventricular ejection fraction prior to and during treatment 3, 4. The FDA label recommends left ventricular ejection fraction measurements prior to initiation of trastuzumab and every 3 months during therapy 4.

In this case, baseline LVEF assessment was performed prior to treatment initiation, and the patient had no history of cardiac disease or risk factors for cardiomyopathy 4. The patient tolerated the full course of neoadjuvant therapy without documented cardiac complications 4. Trastuzumab treatment should be permanently discontinued in patients who develop congestive heart failure or persistent/recurrent LVEF decline 4.

The GeparQuattro study reported that EC-T(X) plus trastuzumab was associated with comparable short-term cardiac toxicity profile as the reference group without trastuzumab 6. A pilot study of preoperative trastuzumab and paclitaxel followed by adjuvant doxorubicin and cyclophosphamide reported four patients who developed grade 2 cardiotoxicity (asymptomatic declines in LVEF), with no unexpected treatment-related noncardiac toxicity 7.

Treatment Response Assessment

This patient achieved excellent response to neoadjuvant therapy, with tumor size reduction from 5.5 cm to 2.0 cm (64% reduction) and complete resolution of axillary lymphadenopathy 3. The post-neoadjuvant ultrasound performed 3 months after completion of chemotherapy showed a 2.0 x 1.8 x 1.3 cm well-defined solid lesion with unremarkable axillary regions 3. This represented downstaging from cT3N1M0 (Stage IIIA) to yT2N0M0 (Stage IIA) 3.

Tumor response should be routinely assessed by clinical exam and imaging studies during delivery of preoperative therapy 3. It is preferred that the standard regimen is completed prior to surgery 3. If all intended treatment is not completed prior to surgery, the remainder may be given in the adjuvant setting 3.

The patient did not achieve pathologic complete response (pCR), defined as absence of invasive tumor in breast and axillary nodes (ypT0/isypN0) 3, 2. However, the significant tumor downstaging and nodal clearance represent an excellent partial response 3. In HER2-positive breast cancer, pCR rates with neoadjuvant trastuzumab-based therapy range from 31.7% to 65.2%, depending on the specific regimen and patient population 3, 6.

The absence of pCR has implications for adjuvant therapy planning. Recent trials such as KATHERINE have demonstrated that patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant therapy benefit from adjuvant trastuzumab emtansine (T-DM1) compared to continued trastuzumab 2. This post-neoadjuvant adjuvant strategy represents an important consideration for this patient 2.

Surgical Management Considerations

Breast-Conserving Surgery vs. Mastectomy

This patient was initially scheduled for breast-conserving surgery (lumpectomy) with frozen section and axillary lymph node dissection, but ultimately opted for modified radical mastectomy 3. This decision reflects the complex interplay between oncologic safety, cosmetic outcomes, patient preference, and psychosocial factors in surgical decision-making 3.

The NSABP B-18 trial showed that breast conservation rates are higher after preoperative chemotherapy 3. If the tumor responds to preoperative chemotherapy, lumpectomy plus axillary lymph node dissection may be considered if the requirements for breast-conserving therapy are fulfilled 3. Requirements for breast-conserving therapy include: ability to achieve negative margins, acceptable cosmetic outcome, absence of extensive intraductal component, absence of multicentric disease, and patient willingness to undergo radiation therapy 3.

In this case, the patient achieved sufficient tumor downstaging (from 5.5 cm to 2.0 cm) to potentially allow breast conservation 3. However, several factors may have influenced the decision toward mastectomy:

1. Residual tumor size of 2.0 cm in a patient with breast size of 152 cm height and 58 kg weight may have resulted in suboptimal cosmetic outcome with lumpectomy 3
2. The presence of skin dimpling on physical examination suggested possible skin involvement, which is a relative contraindication to breast conservation 3
3. The initial tumor size of 5.5 cm with skin thickening on CT imaging raised concerns about extensive disease 3
4. Patient preference and anxiety about local recurrence may have driven the decision toward more extensive surgery 3
5. The 3-month delay between completion of chemotherapy and surgery may have raised concerns about disease progression 3

The NCCN guidelines state that local therapy after a complete or partial response to preoperative systemic therapy usually consists of total mastectomy with level I/II axillary lymph node dissection, with or without delayed breast reconstruction, or lumpectomy and level I/II axillary dissection 3. Both approaches are considered acceptable for clinical stages IIIA (except for T3N1M0), IIIB, or IIIC after clinical response to preoperative systemic therapy 3.

A critical consideration in this case is that the patient did not undergo prechemotherapy sentinel lymph node biopsy 3. If a prechemotherapy sentinel lymph node procedure had been performed and was pathologically negative, then further axillary lymph node staging would not be necessary 3. If a prechemotherapy sentinel lymph node procedure had been performed and was positive, then a level I/II axillary lymph node dissection should be performed 3. In this case, the initial FNA of axillary lymph nodes was falsely negative, and the patient proceeded directly to axillary lymph node dissection at the time of mastectomy 3.

Timing of Surgery: Impact of 3-Month Delay

A notable aspect of this case is the 3-month delay between completion of neoadjuvant chemotherapy (August 7,2025) and surgery (November 14,2025). The patient was initially scheduled for surgery immediately after completing chemotherapy but experienced delays due to "uncontrolled circumstances" 3. This delay raises important questions about optimal timing of surgery after neoadjuvant therapy and potential impact on outcomes 3.

The NCCN guidelines state that it is preferred that the standard regimen is completed prior to surgery, but do not specify an optimal interval between completion of chemotherapy and surgery 3. Most clinical trials of neoadjuvant therapy perform surgery within 3-6 weeks of completing chemotherapy 3, 2. Prolonged delays may theoretically allow for tumor regrowth or development of resistant clones, although data on this issue are limited 3.

In this case, the repeat ultrasound performed 3 months after chemotherapy completion showed stable disease with no evidence of progression 3. The tumor remained 2.0 cm in size, and the axillary nodes remained unremarkable 3. This suggests that the 3-month delay did not result in significant disease progression, likely due to the continued antitumor effect of trastuzumab and the biology of HER2-positive disease 3.

However, this delay represents a potential pitfall in breast cancer management, particularly in resource-limited settings where surgical scheduling, operating room availability, and patient factors may contribute to treatment delays 3. Efforts should be made to minimize the interval between completion of neoadjuvant therapy and definitive surgery to optimize outcomes 3.

Axillary Management

This patient underwent axillary lymph node dissection at the time of mastectomy 3. The initial FNA of axillary lymph nodes was falsely negative, demonstrating the limitation of FNA for nodal staging 3. The CT imaging showed prominent right axillary lymph nodes, and the ultrasound showed enlarged nodes with obliterated hila, both suggesting nodal involvement 3.

The NCCN guidelines recommend pathologic confirmation of malignancy using ultrasound-guided FNA or core biopsy in patients with clinically positive nodes to determine whether axillary lymph node dissection is needed 3. In this case, the FNA was falsely negative, but the high clinical suspicion based on imaging warranted axillary dissection 3.

The post-neoadjuvant ultrasound showed unremarkable axillary regions, suggesting complete nodal response 3. This raises the question of whether sentinel lymph node biopsy alone would have been sufficient in the post-neoadjuvant setting 3. However, the NCCN guidelines state that if prechemotherapy sentinel lymph node staging was not done or was positive, axillary lymph node dissection (category 2A) should be performed 3. Sentinel lymph node procedure in the post-neoadjuvant setting is considered category 3 (based on lower-level evidence) if prechemotherapy axillary lymph node staging was not performed 3.

The final pathology from the mastectomy specimen will be critical in determining the patient's final pathologic stage and guiding adjuvant therapy decisions 3. If the final pathology shows ypT2N0M0 (as suggested by imaging), this would represent an excellent response with complete nodal clearance 3. If residual nodal disease is found, this would have implications for radiation therapy planning and consideration of adjuvant T-DM1 2.

Adjuvant Therapy Planning

Following surgery, this patient will require completion of adjuvant therapy including:

1. Completion of 1 year of trastuzumab therapy 3, 4
2. Adjuvant endocrine therapy for hormone receptor-positive disease 3
3. Radiation therapy based on prechemotherapy characteristics 3
4. Consideration of T-DM1 if residual disease is present 2

Completion of HER2-Targeted Therapy

The patient received 4 cycles of trastuzumab during neoadjuvant therapy (with docetaxel) and should complete a total of 1 year of trastuzumab therapy 3, 4. The NCCN panel recommends up to 1 year of HER2-targeted therapy with trastuzumab 3. Trastuzumab should be administered at 6 mg/kg every 3 weeks to complete 52 weeks of total therapy 4.

Cardiac monitoring should continue during adjuvant trastuzumab therapy with LVEF assessments every 3 months 3, 4. Trastuzumab should be discontinued if the patient develops congestive heart failure or persistent LVEF decline 4.

Adjuvant Endocrine Therapy

This patient has ER-positive (60%) and PR-positive (60%) disease and will benefit from adjuvant endocrine therapy 3. The NCCN guidelines recommend endocrine therapy (category 1) in women with ER- and/or PR-positive tumors 3. Endocrine therapy and trastuzumab can be administered concurrently 3.

For premenopausal women with hormone receptor-positive breast cancer, endocrine therapy options include:

• Tamoxifen with or without ovarian function suppression (OFS) 3
• Aromatase inhibitor with OFS 3

The optimal duration of endocrine therapy is 5-10 years, depending on risk factors and tolerance 3. Extended endocrine therapy beyond 5 years should be considered in patients with node-positive disease or other high-risk features 3.

Radiation Therapy

Radiation therapy is recommended based on prechemotherapy characteristics to the chest wall and supraclavicular lymph nodes 3. The panel recommends strong consideration of including the internal mammary lymph nodes in the radiation therapy field (category 2B) 3. Endocrine therapy and trastuzumab can be administered concurrently with radiation therapy if indicated 3.

In this case, the patient had prechemotherapy T3N1 disease, which warrants postmastectomy radiation therapy 3. Radiation therapy should include the chest wall and regional lymph nodes (supraclavicular and potentially internal mammary nodes) 3. The decision to include internal mammary nodes should be based on tumor location (medial vs. lateral), nodal involvement, and institutional practice patterns 3.

Consideration of T-DM1 for Residual Disease

An important consideration in this patient's adjuvant therapy planning is whether to use trastuzumab emtansine (T-DM1) instead of continuing trastuzumab, based on the presence of residual disease after neoadjuvant therapy 2. The KATHERINE trial demonstrated that patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant therapy benefit from adjuvant T-DM1 compared to continued trastuzumab 2.

In the KATHERINE trial, patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axillary lymph nodes after completing neoadjuvant therapy were randomized to receive adjuvant T-DM1 or trastuzumab for 14 cycles 2. T-DM1 significantly improved invasive disease-free survival compared to trastuzumab (HR 0.50,95% CI 0.39-0.64, P<0.001) 2.

If this patient's final pathology shows residual invasive disease (which is likely given the 2.0 cm residual mass on imaging), she would be a candidate for adjuvant T-DM1 rather than continued trastuzumab 2. This decision should be made in consultation with medical oncology based on the final pathology results and consideration of toxicity, cost, and patient preference 2.

Literature Review: Recent Advances in HER2-Positive Breast Cancer

Neoadjuvant Chemotherapy Trials

The neoadjuvant approach in HER2-positive breast cancer has evolved significantly over the past two decades, with multiple landmark trials establishing the role of HER2-targeted therapy 2. In HER2-positive early breast cancer, neoadjuvant treatment with a combination of sequential chemotherapy and HER2-targeted therapy is currently the standard of care 2.

The NSABP B-27 trial established the benefit of adding docetaxel to anthracycline-based neoadjuvant chemotherapy 3. This 3-arm randomized phase III trial of 2,411 women demonstrated higher rates of complete pathologic response in patients treated preoperatively with 4 cycles of AC followed by 4 cycles of docetaxel versus 4 cycles of preoperative AC alone 3. A disease-free survival advantage was seen (HR 0.71,95% CI 0.55-0.91, P=0.007) that favored preoperative versus postoperative docetaxel in the subset of patients experiencing a clinical partial response to AC 3.

The addition of trastuzumab to neoadjuvant chemotherapy represented a major advance in HER2-positive breast cancer 3, 2. In women with HER2-positive tumors treated with neoadjuvant chemotherapy, the addition of neoadjuvant trastuzumab to paclitaxel followed by FEC chemotherapy was associated with an increase in the pathologic complete response rate from 26% to 65.2% (P=0.016) 3.

The GeparQuattro study prospectively investigated trastuzumab efficacy given simultaneously with anthracycline-taxane-based neoadjuvant chemotherapy in 445 patients with HER2-positive tumors 6. The pathologic complete response rate was 31.7%, which was 16% higher than the reference group without trastuzumab (15.7%) 6. This trial confirmed that combining trastuzumab with anthracycline-taxane-based neoadjuvant chemotherapy results in a high pCR rate without clinically relevant early toxicity 6.

A pilot study of preoperative trastuzumab and paclitaxel followed by adjuvant doxorubicin and cyclophosphamide in 40 women with HER2-positive stage II or III breast cancer achieved clinical response in 75% and complete pathologic response in 18% 7. HER2 3+ tumors were more likely to respond than 2+ tumors (84% vs 38%) 7. This study demonstrated that preoperative trastuzumab and paclitaxel is active against HER2-overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines 7.

Dual HER2 Blockade: Pertuzumab Trials

The addition of pertuzumab to trastuzumab-based neoadjuvant therapy has further improved outcomes in HER2-positive breast cancer 3, 2. The Neosphere trial demonstrated that the addition of pertuzumab to trastuzumab and docetaxel preoperatively led to a statistically significant increase in pCR in the breast, which in turn led to improved outcomes in those with node-positive disease 3.

In the TRYPHAENA trial, preoperative therapy with pertuzumab and trastuzumab given along with anthracycline-containing or anthracycline-free standard chemotherapy regimens showed pCR rates in all treatment arms ranging from 57% to 66% 3. The TRAIN-2 trial showed high pCR rates after treatment regimens with anthracycline plus trastuzumab and pertuzumab (67%) and also without anthracycline plus trastuzumab and pertuzumab (68%) 3.

Based on these results, the NCCN panel supports the FDA-approved indication that a pertuzumab-containing regimen may be administered preoperatively to patients with ≥cT2 or ≥cN1 HER2-positive early-stage breast cancer 3. The addition of pertuzumab may be considered with trastuzumab in those with node-positive disease based on the updated APHINITY trial data 3.

KATHERINE Trial: Post-Neoadjuvant Adjuvant Therapy

The KATHERINE trial represents a paradigm shift in the management of HER2-positive breast cancer with residual disease after neoadjuvant therapy 2. This trial demonstrated that patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant therapy benefit from adjuvant trastuzumab emtansine (T-DM1) compared to continued trastuzumab 2.

This concept of post-neoadjuvant trials is now entering the field of strategies in the neoadjuvant setting for HER2-positive non-metastatic primary breast cancer 2. Depending on pCR or non-pCR after neoadjuvant treatment, the adjuvant therapy may be adjusted 2. This personalized approach allows for treatment escalation in patients with residual disease who are at higher risk for recurrence 2.

Anthracycline-Free Regimens

An important consideration in neoadjuvant therapy for HER2-positive breast cancer is whether anthracyclines are necessary given their cardiac toxicity 3, 8. The TRAIN-2 trial showed similar 3-year event-free survival and overall survival with or without anthracyclines in patients with stage II and III HER2-positive breast cancer 3. Patients who received anthracycline-containing regimen experienced more febrile neutropenia, hypokalemia, and left ventricular ejection fraction decline to grade 2 or worse 3.

Based on these results, considering the added toxicity of anthracycline-containing regimens, the NCCN panel has added nonanthracycline-containing regimens with trastuzumab and pertuzumab as treatment options 3. A multicenter analysis of neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in 84 patients with HER2-positive breast cancer achieved a pCR rate of 47.6% 8. Overall, TCH was well tolerated, with low rates of grade 3-4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported 8.

However, in this case, the patient received an anthracycline-containing regimen (AC followed by docetaxel plus trastuzumab), which remains a standard approach 3. The choice between anthracycline-containing and anthracycline-free regimens should be individualized based on patient risk factors, cardiac function, and institutional protocols 3.

Breast-Conserving Therapy vs. Mastectomy

The NSABP B-18 trial showed that breast conservation rates are higher after preoperative chemotherapy 3. However, preoperative chemotherapy has no demonstrated disease-specific survival advantage over postoperative adjuvant chemotherapy in patients with stage II tumors 3. The primary benefit of neoadjuvant therapy is to enable breast conservation in patients who would otherwise require mastectomy 3.

In this case, the patient achieved sufficient tumor downstaging to potentially allow breast conservation but ultimately chose mastectomy 3. This decision reflects the complex interplay between oncologic safety, cosmetic outcomes, patient preference, and psychosocial factors 3. Both breast-conserving surgery and mastectomy are acceptable options for patients with locally advanced breast cancer who respond to neoadjuvant therapy 3.

Metastatic HER2-Positive Breast Cancer: Emerging Therapies

While this case involves early-stage disease, it is important to note recent advances in metastatic HER2-positive breast cancer that may inform future treatment strategies 1. The combination of trastuzumab, pertuzumab, and a taxane (THP) remains the preferred first-line therapy in most scenarios for metastatic disease 1.

The DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane 1. T-DXd significantly improved progression-free survival and showed a trend towards improved overall survival, establishing this agent as preferred second-line therapy in the metastatic setting 1.

These advances in metastatic disease may eventually translate to the adjuvant and neoadjuvant settings, particularly for patients with high-risk features or residual disease after neoadjuvant therapy 1.

Common Pitfalls and Caveats

Several important pitfalls and caveats are illustrated by this case:

1. Delayed follow-up after initial BI-RADS III finding: The patient was advised to follow up after 6 months but was lost to follow-up, during which time the tumor progressed from 2.0 cm to 5.5 cm 3. BI-RADS III lesions should be followed closely with short-interval imaging (6 months), and any increase in size should prompt immediate biopsy 3.

2. False-negative FNA of axillary lymph nodes: The initial FNA showed no malignant cells despite clinical and imaging evidence of nodal involvement 3. Core needle biopsy is more reliable than FNA for axillary staging and should be preferred when technically feasible 3.

3. Lack of prechemotherapy sentinel lymph node biopsy: The patient did not undergo sentinel lymph node biopsy before starting neoadjuvant therapy, which would have provided definitive nodal staging and potentially allowed for less extensive axillary surgery if nodes were negative 3. Prechemotherapy sentinel lymph node biopsy should be considered in patients with clinically negative nodes to guide surgical planning 3.

4. Delay between completion of chemotherapy and surgery: The 3-month delay between completing neoadjuvant therapy and surgery represents a potential risk for disease progression 3. Efforts should be made to minimize this interval, ideally performing surgery within 3-6 weeks of completing chemotherapy 3.

5. Lack of baseline mammography: Despite being recommended, baseline mammography was not documented as performed 3. Mammography remains an essential component of breast cancer evaluation and should be performed in all patients, even those with dense breast tissue 3.

6. Single-agent HER2 blockade instead of dual blockade: The patient received trastuzumab alone rather than trastuzumab plus pertuzumab, which would have been optimal for node-positive disease 3. Dual HER2 blockade should be considered for all patients with ≥cT2 or ≥cN1 HER2-positive breast cancer undergoing neoadjuvant therapy 3.

7. Lack of genetic testing: Given the patient's young age (35 years) and family history of breast cancer, genetic testing for BRCA1/2 mutations should be strongly considered 1. Genetic testing results may influence surgical decisions (bilateral mastectomy vs. unilateral), surveillance strategies, and family counseling 1.