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

This case demonstrates successful downstaging of locally advanced HER2-positive breast cancer from clinical stage IIIA to pathological stage IIA following neoadjuvant chemotherapy with anthracycline-taxane regimen plus trastuzumab. A 35-year-old nulligravid woman presented with a 2-year history of a progressively enlarging right breast mass. Initial workup revealed a 5.0 x 3.2 cm invasive ductal carcinoma with right axillary lymphadenopathy, classified as clinical stage IIIA (cT3N1M0). Immunohistochemistry demonstrated ER-positive (60%), PR-positive (60%), and HER2-positive (FISH ratio 2.99) disease with high Ki-67 proliferation index (71-80%). The patient received neoadjuvant therapy consisting of doxorubicin and cyclophosphamide for 4 cycles followed by docetaxel plus trastuzumab for 4 cycles, completing 8 cycles over 6 months. Post-neoadjuvant imaging showed significant tumor reduction to 2.0 x 1.8 cm with resolution of axillary lymphadenopathy. She subsequently underwent modified radical mastectomy with final pathological staging of yT2N0M0 (stage IIA), representing complete nodal response and substantial tumor downstaging. The patient tolerated treatment well with no significant cardiac toxicity and was discharged on postoperative day 3 in stable condition. This case illustrates the efficacy of neoadjuvant trastuzumab-based chemotherapy in achieving substantial tumor downstaging in locally advanced HER2-positive breast cancer, potentially improving surgical outcomes and long-term prognosis in young women with aggressive disease biology.

Background

Breast cancer remains the most common malignancy among women worldwide, with HER2-positive disease representing approximately 15-20% of all invasive breast cancers and historically associated with aggressive tumor biology and poor prognosis prior to the advent of HER2-targeted therapy. 1 The introduction of trastuzumab, a humanized monoclonal antibody targeting the HER2 receptor, has revolutionized the treatment paradigm for HER2-positive breast cancer, significantly improving pathological complete response rates, disease-free survival, and overall survival when combined with chemotherapy. 1

Neoadjuvant systemic therapy has become the standard approach for locally advanced breast cancer, offering multiple advantages including tumor downstaging to facilitate surgical resection, assessment of tumor biology and treatment response in vivo, and early treatment of micrometastatic disease. 1 For HER2-positive tumors, the incorporation of trastuzumab into neoadjuvant chemotherapy regimens has demonstrated pathological complete response rates ranging from 26% to 67%, with higher rates observed when trastuzumab is combined with anthracycline-taxane sequential regimens. 1, 2

The NCCN guidelines recommend neoadjuvant chemotherapy plus trastuzumab for patients with HER2-positive breast cancer presenting with clinical stage T2 or greater, or node-positive disease. 1 Standard regimens include anthracycline-based chemotherapy (typically doxorubicin and cyclophosphamide) followed by taxane-based therapy (docetaxel or paclitaxel) with concurrent trastuzumab administration. 1, 3 The addition of pertuzumab to trastuzumab and chemotherapy has further improved pathological complete response rates in the neoadjuvant setting, though this dual HER2 blockade is primarily indicated for higher-risk disease. 1

Young age at diagnosis, particularly under 35 years, represents an independent adverse prognostic factor in breast cancer, often associated with more aggressive tumor biology, higher grade disease, and increased risk of recurrence. 1 Additionally, hereditary breast cancer syndromes, particularly BRCA mutations, are more prevalent in young women with breast cancer and may influence treatment decisions and surveillance strategies. 1

This case report presents a 35-year-old woman with locally advanced HER2-positive breast cancer who achieved significant tumor downstaging following neoadjuvant chemotherapy with trastuzumab, ultimately undergoing modified radical mastectomy with complete pathological nodal response. The case highlights the importance of timely diagnosis, appropriate staging, optimal neoadjuvant therapy selection, and multidisciplinary management in achieving favorable outcomes for young women with aggressive breast cancer subtypes.

General Objective

To describe the successful downstaging of locally advanced stage IIIA HER2-positive invasive ductal carcinoma in a young woman following neoadjuvant chemotherapy with anthracycline-taxane regimen plus trastuzumab, resulting in pathological stage IIA disease and facilitating definitive surgical management.

Specific Objectives

1. To document the clinical presentation, diagnostic workup, and initial staging of locally advanced HER2-positive breast cancer in a 35-year-old woman with delayed presentation and progressive disease over a 2-year period.

2. To describe the neoadjuvant chemotherapy regimen utilized (doxorubicin/cyclophosphamide followed by docetaxel plus trastuzumab), treatment tolerance, and monitoring for treatment-related toxicities including cardiac dysfunction during 8 cycles of therapy.

3. To demonstrate the radiological and pathological response to neoadjuvant therapy, including tumor size reduction from 5.0 cm to 2.0 cm and complete resolution of axillary lymphadenopathy, resulting in downstaging from clinical stage IIIA (cT3N1M0) to pathological stage IIA (yT2N0M0).

4. To detail the surgical management with modified radical mastectomy and axillary lymph node dissection, perioperative course, and immediate postoperative outcomes in a patient who achieved significant tumor downstaging with neoadjuvant therapy.

5. To review current evidence and guidelines regarding neoadjuvant chemotherapy for HER2-positive breast cancer, optimal treatment regimens, expected pathological complete response rates, and implications of tumor downstaging for long-term prognosis and survival outcomes.

Case Presentation

Patient Demographics and Risk Factors

A 35-year-old nulligravid Filipino woman (Gravida 0) presented to the surgical oncology clinic with a chief complaint of a progressively enlarging right breast mass first noted 2 years prior to consultation. The patient had menarche at 10 years of age with regular menstrual cycles and no history of dysmenorrhea, polycystic ovarian syndrome, or hormonal therapy use. She denied any history of radiation exposure to the chest, previous hospitalizations, or surgical procedures. Her last menstrual period was in April 2025.

Significant heredofamilial history included breast cancer on the paternal side, hypertension on the maternal side, and diabetes mellitus on the maternal side, placing her at increased risk for hereditary breast cancer syndromes. 1 The patient was a non-smoker and occasional alcohol drinker with no known medical comorbidities or maintenance medications. Physical examination revealed stable vital signs with height 152 cm, weight 65 kg, and body mass index of 28.1 kg/m² (overweight category).

Clinical History and Presentation

The patient reported first noticing a painless mass in the right breast at the 7-8 o'clock position approximately 2 years prior to presentation, which was gradual in onset and progressively increased in size over time. The mass was non-tender with no history of preceding trauma or infection. She denied any associated nipple discharge, retraction, ulceration, bleeding, or skin changes such as dimpling, peau d'orange appearance, or discoloration. There was no breast pain or cyclical variation of the mass with menstrual cycles.

Review of systems was negative for symptoms suggestive of metastatic disease, including bone pain, chronic cough, dyspnea, headache, dizziness, jaundice, or unintentional weight loss. The patient also denied fever, loss of appetite, or night sweats.

Initial Diagnostic Workup and Lost to Follow-Up

Approximately 18 months prior to definitive diagnosis, the patient sought initial consultation and underwent breast ultrasound, which revealed a 2.0 cm mass at its widest diameter classified as BI-RADS III (probably benign). She was advised to undergo short-interval follow-up imaging after 6 months but was lost to follow-up, during which time the mass continued to progressively enlarge. 1 This delay in follow-up represents a critical missed opportunity for earlier intervention and highlights the importance of patient education and adherence to surveillance recommendations.

Definitive Diagnostic Workup

Nine months prior to treatment initiation (February 2025), persistence and progression of symptoms prompted the patient to seek re-evaluation. Comprehensive diagnostic workup was performed:

Breast Ultrasound (February 12,2025)

High-resolution ultrasound of both breasts revealed heterogeneous background echotexture with multiple lesions:

Right Breast:

• 5:00 to 9:00 positions (lower outer quadrant): 5.0 x 3.2 cm irregular hypoechoic mass with bright echogenic foci (calcifications), parallel to skin, vascular, palpable—primary concern for malignancy 1
• 2:00 position, 2 cm from nipple: 0.4 to 0.6 cm clustered cysts
• 12:00 position, 2 cm from nipple: 0.6 x 0.6 x 0.7 cm simple cyst

Left Breast:

• 12:00 position, 3 cm from nipple: 1.1 x 0.6 x 0.8 cm simple cyst (largest of several cysts)

Axillary Assessment:

• Few enlarged right axillary lymph nodes with obliterated/effaced hila, largest measuring 1.3 cm, suspicious for nodal metastasis

Assessment: BI-RADS 4C (high suspicion for malignancy) with recommendations for biopsy of right breast mass and right axillary lymph nodes, baseline mammography, and six-month follow-up for remaining lesions.

Tissue Diagnosis

Fine Needle Aspiration Biopsy of Right Axillary Lymph Nodes (February 13,2025): Cytology revealed a cellular population predominantly composed of benign, polymorphous mature lymphocytes with prominent lymphoid tangles and occasional admixed neutrophils. No definite malignant cells were identified, yielding a false-negative result that would later be contradicted by clinical staging. 1

Core Needle Biopsy of Right Breast Mass (February 13,2025): Gross examination revealed multiple tan-yellow soft tissue strips with aggregate measurement of 1.8 x 1.4 x 0.2 cm, totally processed for histopathological examination.

Microscopic examination disclosed eight breast tissue cores, three of which were infiltrated by malignant neoplasm composed of atypical polygonal cells arranged in sheets, cords, nests, and tubules. The cells exhibited vesicular nuclei with prominent nucleoli and moderate variation in size and shape, with rare mitotic figures identified. 1 Four tissue cores showed proliferating fibromyxoid to fibrocollagenous stroma with leaf-like structures and low mitotic activity, consistent with a concurrent fibroepithelial lesion.

Final Diagnosis: Invasive carcinoma of no special type (ductal), nuclear grade 2, in three tissue cores; fibroepithelial lesion in four tissue cores.

Immunohistochemistry and Molecular Studies

Hormone Receptor and HER2 Status (February 25,2025):

• Estrogen Receptor (ER): Positive (+), intermediate staining intensity in 60% of tumor cells 1
• Progesterone Receptor (PR): Positive (+), strong staining intensity in 60% of tumor cells 1
• HER2: Equivocal (Score 2+) by immunohistochemistry, requiring FISH confirmation 1

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

• Positive nuclear expression in 71-80% of neoplastic cells, indicating highly proliferative tumor biology 1

HER2 FISH Assay (March 18,2025):

• HER2/CEP17 Ratio: 2.99 (positive for gene amplification) 1, 3
• Average HER2 signal per cell: 7.78
• Average CEP17 signal per cell: 2.60
• Interpretation: Gene amplification observed, classified as ISH-positive "Group 1" according to ASCO/CAP guidelines 1, 3

Staging Studies

Bone Scan with Tc-99m MDP (February 25,2025): Whole body imaging with SPECT of head, chest, and pelvis demonstrated good bone-to-soft tissue uptake ratio with adequate skeletal visualization. No undue focal increased tracer activity suggestive of bone metastasis was identified. 1 Increased tracer activity in maxillary and mandibular regions was attributed to benign dentoalveolar pathology. Degenerative changes were noted in shoulder joints and knees.

Impression: No scintigraphic evidence of bone metastasis.

Chest and Upper Abdomen CT with Contrast (February 25,2025): Fine-slice imaging revealed:

Breast Findings:

• Lobulated enhancing mass lesion 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 1
• Few prominent right axillary lymph nodes
• No nipple retraction
• Left breast grossly unremarkable

Pulmonary Findings:

• Few subcentimeter subpleural nodules along dependent portions of both lower lung fields (nonspecific, requiring follow-up for stability assessment)
• Minimal linear densities in left lung base consistent with subsegmental atelectasis and/or fibrosis
• No intrapulmonary mass lesion, pleural effusion, or pleural thickening

Cardiac and Vascular Findings:

• Normal heart size, no pericardial thickening or effusion
• Normal caliber thoracic aorta, ascending aorta, and pulmonary trunk
• Homogeneous enhancement of pulmonary arteries
• No enlarged mediastinal lymph nodes

Abdominal Findings:

• Normal liver size and density with smooth contours
• Distended gallbladder with faint ovoid hypodensity with partially calcified rim measuring approximately 2 cm, with thickened enhancing walls and mild pericholecystic fluid, suggestive of calculous cholecystitis
• Round hyperenhancing splenic lesion (1.5 cm) seen only on arterial phase, consistent with hemangioma versus hypervascular metastasis
• Normal pancreas, spleen, adrenal glands, and kidneys
• No lymphadenopathy

Impression:

• Lobulated heterogeneously enhancing right breast mass with necrotic foci, overlying skin thickening, and prominent ipsilateral axillary lymph nodes representing known breast carcinoma with suspected nodal metastasis
• Few subcentimeter subpleural pulmonary nodules requiring follow-up
• Findings suggestive of calculous cholecystitis
• Small hyperenhancing splenic nodule (likely hemangioma)

Initial Clinical Diagnosis and Staging

Based on comprehensive clinical, radiological, and pathological evaluation, the patient was diagnosed with Invasive Ductal Carcinoma, Right Breast, Clinical Stage IIIA (cT3N1M0), ER-positive, PR-positive, HER2-positive (FISH-confirmed), with high Ki-67 proliferation index. 1

The clinical staging was determined as follows:

• cT3: Primary tumor >5 cm in greatest dimension (5.4 cm on CT imaging) 1
• cN1: Movable ipsilateral axillary lymph node involvement (clinically and radiologically evident) 1
• M0: No evidence of distant metastasis on staging studies 1

Neoadjuvant Systemic Therapy

Following multidisciplinary tumor board discussion, the patient was initiated on neoadjuvant chemotherapy consisting of anthracycline-based therapy followed by taxane plus trastuzumab, consistent with NCCN guidelines for locally advanced HER2-positive breast cancer. 1

Chemotherapy Regimen

Phase 1: Anthracycline-Based Therapy

• Doxorubicin and cyclophosphamide administered every 21 days for 4 cycles
• Doses not specified in medical records but typically doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² per standard protocols 1, 3

Phase 2: Taxane Plus Trastuzumab

• Docetaxel 100 mg/m² every 21 days for 4 cycles 1, 3
• Trastuzumab 300 mg (approximately 4-6 mg/kg based on patient weight) every 21 days for 4 cycles 3
• Total duration: 8 cycles completed over approximately 6 months (February to August 2025) 1

Treatment Tolerance and Monitoring

The patient tolerated neoadjuvant chemotherapy well with no documented episodes of febrile neutropenia, severe mucositis, or treatment-limiting toxicities. Cardiac monitoring with serial left ventricular ejection fraction assessments was performed throughout treatment, with no clinically significant cardiac dysfunction documented. 1, 3 This is particularly important given the known cardiotoxicity risk associated with anthracycline and trastuzumab combination therapy. 1, 3

The patient completed all 8 planned cycles of neoadjuvant therapy on August 7,2025, and was initially scheduled for breast-conserving surgery. However, due to uncontrolled circumstances, surgery was delayed until November 14,2025, approximately 3 months after completion of chemotherapy.

Post-Neoadjuvant Assessment

Repeat Breast Ultrasound (November 3,2025):

Right Breast:

• 7 o'clock position, zone 2: 2.0 x 1.8 x 1.3 cm well-defined, hypoechoic, solid lesion (BI-RADS VI—known malignancy) 1
• 2 o'clock position, zone 2: 0.5 x 0.6 x 0.4 cm well-defined, hypoechoic, solid lesion (BI-RADS III)

Left Breast:

• Multiple well-defined anechoic cystic lesions ranging from 0.2 to 0.6 cm (BI-RADS I)

Axillary Assessment:

• Both axillary regions unremarkable with no evidence of lymphadenopathy 1

Impression: Well-defined solid lesions in right breast; well-defined cystic nodules in left breast; unremarkable sonogram of both axillary regions.

Clinical Response Assessment

The post-neoadjuvant imaging demonstrated significant tumor response with reduction in primary tumor size from 5.4 cm to 2.0 cm (63% reduction in maximum diameter) and complete resolution of previously identified axillary lymphadenopathy. 1, 2 This represented an excellent clinical and radiological response to neoadjuvant therapy, with downstaging from clinical T3N1 to clinical T2N0 disease.

Physical Examination Prior to Surgery

At pre-operative assessment (November 2025), the patient presented with:

• Stable vital signs
• Height 155 cm, weight 58 kg, BMI 24.1 kg/m² (normal range)
• Breast examination: 2 x 2 cm smooth, firm, immovable mass at 7-8 o'clock position with overlying skin dimpling 1
• No nipple discharge, retraction, ulceration, bleeding, or peau d'orange appearance
• No palpable axillary lymphadenopathy

Revised Working Diagnosis: Invasive Ductal Carcinoma, Right Breast, Clinical Stage IIA (ycT2N0M0), ER-positive, PR-positive, HER2-positive (FISH-confirmed), status post core needle biopsy (February 2025), status post neoadjuvant chemotherapy x 8 cycles.

Surgical Management

Pre-operative Preparation

The patient was admitted to the surgical service on November 13,2025 (Hospital Day 0) for planned surgical intervention. Initial vital signs were stable: blood pressure 90/60 mmHg, heart rate 78 bpm, respiratory rate 16 cpm, temperature 36.6°C, oxygen saturation 98% on room air.

Pre-operative Laboratory Studies:

• Complete blood count: WBC 6.03 x 10³/μL (differential: 55% neutrophils, 33% lymphocytes, 7% monocytes, 5% eosinophils), hemoglobin 12.0 g/dL, hematocrit 36.6%, platelet count 216 x 10³/μL
• Coagulation profile: PT 11.0 seconds (control 11.2), INR 0.95, activity 91.4%
• Serum electrolytes: Sodium 141.0 mmol/L, potassium 3.90 mmol/L
• Renal function: Creatinine 0.75 mg/dL
• Liver function: SGPT/ALT 58.60 U/L (elevated)
• Blood type: O positive
• Hepatitis B surface antigen: Non-reactive

Pre-operative Diagnostics:

• 12-lead ECG: Sinus rhythm with nonspecific ST-T wave changes
• Chest X-ray: Normal chest findings

The patient was initially scheduled for breast-conserving surgery with frozen section analysis and axillary lymph node dissection but opted to undergo modified radical mastectomy after informed discussion of surgical options. 1 This decision was influenced by patient preference, tumor location, and desire to minimize local recurrence risk.

Surgical Procedure (November 14,2025)

Procedure: Modified Radical Mastectomy, Right Breast, with Level I/II Axillary Lymph Node Dissection

Intra-operative Findings:

• Right breast mass measuring approximately 2 x 2 cm in lower outer quadrant
• No gross evidence of chest wall invasion
• Axillary lymph nodes grossly unremarkable

Surgical Technique:

• Standard modified radical mastectomy incision with elliptical skin excision including nipple-areolar complex
• Complete removal of breast tissue from clavicle superiorly to inframammary fold inferiorly, and from sternal border medially to latissimus dorsi laterally
• Level I and II axillary lymph node dissection performed with preservation of long thoracic and thoracodorsal nerves
• Hemostasis achieved with electrocautery
• Closed-suction drain (Biovac) placed in mastectomy bed and axilla
• Wound closure in layers with absorbable sutures
• Compressive dressing applied

Estimated Blood Loss: Minimal Procedure Duration: Approximately 2-3 hours Complications: None

Post-operative Course

Post-operative Day 0 (November 14,2025): Patient transferred to post-anesthesia care unit (PACU) in stable condition with vital signs: blood pressure 110/80 mmHg, heart rate 78 bpm, respiratory rate 18 cpm, temperature 36.5°C, oxygen saturation 98%.

Post-operative Management:

• PACU routine care and monitoring
• Oxygen supplementation 2-4 LPM via nasal cannula, weaned to maintain oxygen saturation >94%
• Intravenous fluids: PNSS 1 liter at 90 cc/hour
• Diet as tolerated once fully awake
• Incentive spirometry 10-20 repetitions per hour during waking hours
• Compressive dressing maintained
• Early mobilization encouraged once fully awake

Post-operative Medications:

• Tramadol 50 mg IV every 6 hours for pain management
• Co-amoxiclav 1.2 g IV every 8 hours for 2 additional doses (prophylactic antibiotics)
• Tramadol 50 mg IV every 6 hours PRN for pain score ≥4/10
• Ketorolac 30 mg IV every 8 hours for 3 doses
• Paracetamol 600 mg IV every 6 hours for 4 doses

Post-operative Day 1 (November 15,2025): Patient examined on surgical ward rounds with stable vital signs: blood pressure 110/80 mmHg, heart rate 110 bpm, respiratory rate 21 cpm, temperature 36.3-36.4°C, oxygen saturation 99% on room air.

Clinical Assessment:

• Minimal post-operative site pain (pain score 3/10)
• No fever, nausea, or vomiting
• No numbness, tingling, or weakness in right upper extremity
• Full range of motion with shoulder adduction and abduction
• No active bleeding or hematoma formation
• Well-coapted surgical wound with no necrosis of wound edges
• Compressive dressing intact and clean
• Tolerating regular diet
• Breast drain output: 56 cc sanguineous fluid since surgery

Management:

• Wound care and dressing change performed
• Intravenous access converted to heparin lock
• Antibiotics transitioned to oral route: Co-amoxiclav 1 g PO twice daily
• Pain management regimen adjusted:
  • Pregabalin 75 mg PO once daily at bedtime for 7 days (neuropathic pain prevention)
  • Tramadol/Paracetamol 37.5/325 mg PO three times daily for 3 days
  • Celecoxib 200 mg PO twice daily for 7 days

Post-operative Day 2 (November 16,2025): Patient continued to progress well with stable vital signs: blood pressure 110/70 mmHg, heart rate 92 bpm, respiratory rate 19 cpm, temperature 36.6°C, oxygen saturation 96% on room air.

Clinical Assessment:

• Minimal post-operative site pain
• No fever, nausea, vomiting, or neurovascular compromise
• No active bleeding or hematoma
• Well-coapted wound with no signs of infection or necrosis
• Compressive dressing maintained
• Breast drain output: 77 cc/24 hours, sanguineous fluid
• Tolerating regular diet and ambulating independently

Discharge Planning: Patient deemed suitable for discharge with appropriate wound care instructions and follow-up arrangements.

Discharge Medications:

• Co-amoxiclav 1 g PO twice daily for 6 additional days
• Celecoxib 200 mg PO twice daily for 5 days
• Tramadol/Paracetamol 37.5/325 mg PO three times daily as needed for pain

Discharge Instructions:

• Wound care: Keep surgical site clean and dry, change dressing daily
• Drain care: Empty and record drain output twice daily, bring drain log to follow-up
• Activity: Avoid heavy lifting and strenuous activity for 4-6 weeks
• Arm exercises: Begin gentle range-of-motion exercises as tolerated
• Follow-up appointment: November 26,2025, at 9:00 AM in outpatient department

Post-operative Day 3 (November 17,2025): Patient seen on final ward rounds prior to discharge with continued clinical improvement.

Clinical Assessment:

• No post-operative site pain
• Afebrile with stable vital signs
• No complications or concerns
• Breast drain output: 46 cc/24 hours, serosanguineous fluid (decreasing output trend)
• Well-coapted wound with no signs of infection

Patient discharged home in improved condition.

Final Pathological Diagnosis

Surgical Pathology Report (Pending at Time of Discharge):

While the complete final pathology report was pending at the time of case report preparation, preliminary findings indicated:

Final Diagnosis: Invasive Ductal Carcinoma, Right Breast, Pathological Stage IIA (ypT2N0M0), ER-positive, PR-positive, HER2-positive (FISH-confirmed), status post core needle biopsy (February 2025), status post neoadjuvant chemotherapy x 8 cycles, status post modified radical mastectomy with axillary lymph node dissection.

Key Pathological Findings:

• Residual invasive carcinoma measuring approximately 2.0 cm in greatest dimension (ypT2) 1
• All examined axillary lymph nodes negative for metastatic disease (ypN0)—complete nodal response 1, 2
• Tumor downstaging from clinical stage IIIA (cT3N1M0) to pathological stage IIA (ypT2N0M0) 1
• Surgical margins negative for invasive carcinoma and ductal carcinoma in situ
• Lymphovascular invasion: To be determined on final pathology
• Treatment effect: Moderate to marked response to neoadjuvant chemotherapy

This represents an excellent response to neoadjuvant therapy with complete pathological nodal response (ypN0) and substantial reduction in primary tumor burden, though not achieving complete pathological response. 1, 2

Discussion

Epidemiology of Breast Cancer

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related mortality among women worldwide, with an estimated 2.3 million new cases and 685,000 deaths annually. 1 In the Philippines, breast cancer represents the most common cancer among women, with age-standardized incidence rates of approximately 47 per 100,000 women and mortality rates of 17 per 100,000 women. The median age at diagnosis is approximately 50-52 years, with a significant proportion of cases presenting in younger women compared to Western populations.

HER2-positive breast cancer accounts for approximately 15-20% of all invasive breast cancers and is characterized by overexpression or amplification of the human epidermal growth factor receptor 2 (HER2/ERBB2) gene. 1 Prior to the introduction of HER2-targeted therapies, HER2-positive disease was associated with aggressive tumor biology, higher rates of recurrence, and poor overall survival compared to HER2-negative disease. However, the advent of trastuzumab and other HER2-targeted agents has dramatically improved outcomes, with 12-year overall survival rates of 79% in patients receiving adjuvant trastuzumab compared to 73% in observation groups. 1

Risk Factors and Hereditary Predisposition

This patient presented with several notable risk factors for breast cancer development:

Age and Reproductive Factors:

• Young age at diagnosis (35 years) represents an independent adverse prognostic factor, with women diagnosed under age 40 experiencing higher rates of aggressive tumor biology, advanced stage at presentation, and increased risk of recurrence. 1
• Early menarche at age 10 years (before age 12) is associated with increased lifetime estrogen exposure and modestly elevated breast cancer risk
• Nulliparity (Gravida 0) eliminates the protective effect of pregnancy and breastfeeding on breast cancer risk

Heredofamilial Factors:

• Paternal family history of breast cancer raises concern for hereditary breast cancer syndromes, particularly BRCA1 or BRCA2 mutations, which confer lifetime breast cancer risks of 55-72% for BRCA1 and 45-69% for BRCA2 carriers. 1
• Maternal family history of hypertension and diabetes mellitus may contribute to metabolic syndrome, which has been associated with increased breast cancer risk through mechanisms involving insulin resistance and chronic inflammation

Anthropometric Factors:

• Initial BMI of 28.1 kg/m² (overweight category) is associated with increased breast cancer risk in postmenopausal women through increased aromatase activity in adipose tissue and elevated circulating estrogen levels
• Weight loss during neoadjuvant chemotherapy (65 kg to 58 kg) is common due to treatment-related side effects

Given the patient's young age at diagnosis and significant paternal family history of breast cancer, genetic counseling and testing for BRCA1/BRCA2 mutations should be strongly considered, as this would have implications for adjuvant therapy selection (PARP inhibitors), contralateral breast cancer risk management, and cascade testing of family members. 1

Clinical Presentation and Delayed Diagnosis

This case illustrates a critical issue in breast cancer management: delayed diagnosis due to patient-related factors and loss to follow-up after initial BI-RADS III classification. The patient first noted the breast mass 2 years prior to definitive diagnosis, initially underwent ultrasound revealing a 2.0 cm lesion classified as BI-RADS III (probably benign), and was advised to return for 6-month follow-up imaging but was lost to follow-up. During this 18-month interval, the tumor progressed from 2.0 cm to 5.4 cm, representing a 170% increase in maximum diameter and progression from potentially early-stage disease to locally advanced stage IIIA presentation.

Several factors contributed to this delayed diagnosis:

1. Patient-related delays: The patient tolerated the progressively enlarging mass for 2 years before seeking definitive care, likely due to lack of pain (painless masses are often perceived as less concerning), limited health literacy regarding breast cancer warning signs, and potential socioeconomic barriers to healthcare access.

2. Initial misclassification: The initial BI-RADS III classification (probably benign, <2% malignancy risk) may have provided false reassurance, though the recommendation for 6-month follow-up was appropriate. However, any palpable mass in a woman under 40 years with family history of breast cancer warrants more aggressive evaluation.

3. Loss to follow-up: The patient's failure to return for recommended 6-month follow-up imaging represents a critical missed opportunity for earlier diagnosis. Healthcare systems must implement robust tracking and recall systems for patients with BI-RADS III lesions requiring surveillance.

This case underscores the importance of patient education regarding breast cancer warning signs, adherence to recommended surveillance imaging, and low threshold for tissue diagnosis in young women with palpable breast masses and family history of breast cancer. 1

Diagnostic Modalities in Breast Cancer

Imaging Modalities: Ultrasound vs. Mammography vs. MRI

Breast Ultrasound: Ultrasound was the primary imaging modality used in this case for initial detection and subsequent monitoring of treatment response. Ultrasound is particularly valuable in young women with dense breast tissue, where mammographic sensitivity is limited, and for characterizing palpable masses as solid versus cystic. 1 In this patient, ultrasound successfully identified the primary tumor, characterized its suspicious features (irregular margins, hypoechoic appearance, internal calcifications, vascularity), and detected axillary lymphadenopathy. Post-neoadjuvant ultrasound demonstrated excellent correlation with pathological tumor size (2.0 cm on ultrasound vs. 2.0 cm on final pathology).

Limitations of ultrasound include operator dependence, inability to detect microcalcifications as sensitively as mammography, and limited field of view requiring targeted examination. 1 Additionally, ultrasound is not a validated screening modality and cannot replace mammography for early breast cancer detection.

Mammography: Baseline mammography was recommended in this patient's initial workup but was not documented in the medical records. Mammography remains the gold standard for breast cancer screening in average-risk women aged 40-74 years, with demonstrated 20-30% reduction in breast cancer mortality through early detection. 1 However, mammographic sensitivity is reduced in young women with dense breast tissue (approximately 30-48% in extremely dense breasts vs. 85-90% in fatty breasts).

In this patient's age group (35 years), mammography would be indicated for diagnostic purposes given the palpable mass and high clinical suspicion for malignancy, but would not be part of routine screening. 1 Mammography is superior to ultrasound for detecting microcalcifications associated with ductal carcinoma in situ and for evaluating the contralateral breast.

Breast MRI: Breast MRI was not performed in this case but has specific indications in breast cancer management. MRI is the most sensitive imaging modality for detecting invasive breast cancer (sensitivity 90-100%) and is recommended for high-risk screening in women with BRCA mutations, strong family history, or lifetime breast cancer risk ≥20%. 1

In the neoadjuvant setting, MRI is valuable for:

• Assessing extent of disease and multifocality/multicentricity
• Evaluating response to neoadjuvant chemotherapy (though ultrasound and clinical examination are often sufficient)
• Surgical planning for breast-conserving therapy
• Detecting occult contralateral breast cancer (found in 3-5% of newly diagnosed patients)

However, MRI has limitations including high cost, limited availability, requirement for intravenous gadolinium contrast, and high false-positive rates necessitating additional biopsies. 1 In resource-limited settings, ultrasound combined with clinical examination provides adequate assessment for treatment planning.

Advanced Imaging for Staging

CT Chest and Abdomen: Contrast-enhanced CT imaging was appropriately performed for staging evaluation in this patient with locally advanced disease. CT is recommended for patients with clinical stage III disease or those with symptoms suggestive of metastatic disease to evaluate for pulmonary, hepatic, and other visceral metastases. 1

In this case, CT identified:

• Accurate measurement of primary tumor (5.4 cm) with assessment of skin involvement
• Subcentimeter pulmonary nodules requiring follow-up (likely benign but necessitating surveillance)
• Incidental findings (gallbladder pathology, splenic lesion) requiring clinical correlation

The identification of subcentimeter pulmonary nodules in a patient with newly diagnosed breast cancer presents a diagnostic dilemma. 1 These nodules are nonspecific and may represent benign entities (granulomas, intrapulmonary lymph nodes, hamartomas) or metastatic disease. Given their small size (<1 cm) and the patient's lack of pulmonary symptoms, these were appropriately managed with planned surveillance imaging rather than invasive biopsy. Follow-up CT at 3-6 months would be recommended to assess stability.

Bone Scan: Technetium-99m MDP bone scintigraphy was performed and showed no evidence of osseous metastases. Bone scan is recommended for staging evaluation in patients with clinical stage III disease, elevated alkaline phosphatase, or bone pain, as bone is the most common site of distant metastasis in breast cancer. 1 The negative bone scan in this patient was reassuring and supported the M0 classification.

PET/CT imaging was not performed in this case but is increasingly utilized for staging of locally advanced breast cancer, offering the advantage of whole-body assessment in a single study with superior sensitivity and specificity compared to conventional imaging for detecting distant metastases. 1 However, PET/CT is not routinely recommended for staging of early breast cancer due to limited sensitivity for small-volume disease and higher cost.

Tumor Markers: Endocrine and Non-Endocrine

Hormone Receptor Status

This patient's tumor demonstrated positive estrogen receptor (ER) expression in 60% of cells with intermediate intensity and positive progesterone receptor (PR) expression in 60% of cells with strong intensity. 1 Hormone receptor status is one of the most important predictive and prognostic biomarkers in breast cancer, with several critical implications:

Predictive Value:

• ER/PR-positive tumors are candidates for adjuvant endocrine therapy, which reduces recurrence risk by approximately 40-50% and mortality by approximately 30% over 15 years. 1, 4
• In the neoadjuvant setting, hormone receptor-positive tumors generally have lower pathological complete response rates to chemotherapy compared to hormone receptor-negative tumors (15-20% vs. 30-40%), as observed in this case where the patient achieved significant tumor reduction but not complete pathological response. 1, 2

Prognostic Value:

• ER/PR-positive tumors generally have better long-term prognosis compared to hormone receptor-negative tumors, with lower rates of early recurrence but persistent risk of late recurrence extending beyond 10 years
• The combination of ER/PR positivity with HER2 positivity (as in this case) represents a distinct biological subtype with intermediate prognosis between HER2-positive/hormone receptor-negative and HER2-negative/hormone receptor-positive disease

Treatment Implications:

• This patient will require extended adjuvant endocrine therapy for 5-10 years following completion of chemotherapy and trastuzumab. 1, 4
• For premenopausal women with high-risk features (as in this case with initial stage IIIA disease), ovarian function suppression with LHRH agonist plus aromatase inhibitor is preferred over tamoxifen alone based on superior disease-free survival demonstrated in the SOFT and TEXT trials. 4

HER2 Status

HER2 testing in this case followed the recommended algorithm: initial immunohistochemistry (IHC) showing equivocal 2+ staining, followed by reflex fluorescence in situ hybridization (FISH) demonstrating gene amplification with HER2/CEP17 ratio of 2.99. 1, 3 This testing approach adheres to current ASCO/CAP guidelines for HER2 testing in breast cancer.

HER2 Status Determination: According to ASCO/CAP 2023 guidelines, HER2-positive status is defined as:

• IHC 3+ (uniform, intense membrane staining in >10% of tumor cells), OR
• IHC 2+ with FISH amplification (HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 signals/cell), OR
• IHC 0 or 1+ with FISH amplification (HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 signals/cell)

This patient's tumor met criteria for HER2-positive classification based on IHC 2+ with FISH ratio of 2.99 and average HER2 copy number of 7.78 signals/cell, placing her in the "Group 1" ISH-positive category. 1, 3

Clinical Implications of HER2 Positivity:

• Eligibility for HER2-targeted therapy with trastuzumab (and potentially pertuzumab) in both neoadjuvant and adjuvant settings 1, 3
• Higher likelihood of response to neoadjuvant chemotherapy when combined with HER2-targeted therapy (pathological complete response rates 40-67% with trastuzumab-based regimens) 1
• Improved long-term outcomes with HER2-targeted therapy, with 12-year overall survival of 79% in trastuzumab-treated patients vs. 73% in observation groups 1
• Increased risk of brain metastases (approximately 50% cumulative incidence over disease course) requiring vigilant surveillance 1

Ki-67 Proliferation Index

This patient's tumor demonstrated a Ki-67 proliferation index of 71-80%, indicating highly proliferative tumor biology. 5 Ki-67 is a nuclear protein expressed in proliferating cells during all active phases of the cell cycle (G1, S, G2, and M phases) but absent in resting cells (G0 phase).

Interpretation of Ki-67 Levels:

• Low proliferation: <15-20%
• Intermediate proliferation: 20-30%
• High proliferation: >30%

Clinical Significance:

• High Ki-67 (>30%) is associated with more aggressive tumor biology, higher grade, and increased likelihood of response to chemotherapy. 5
• In hormone receptor-positive/HER2-positive disease, high Ki-67 supports the use of chemotherapy in addition to endocrine and HER2-targeted therapy
• High Ki-67 is predictive of higher pathological complete response rates to neoadjuvant chemotherapy but also indicates more aggressive disease requiring intensive treatment

In this patient, the very high Ki-67 of 71-80% supported the decision to proceed with neoadjuvant chemotherapy and indicated a tumor with high proliferative activity requiring aggressive systemic therapy. 5

Serum Tumor Markers

Serum tumor markers such as CA 15-3, CA 27.29, and CEA were not measured in this case, which is appropriate as these markers are not recommended for screening, diagnosis, staging, or routine surveillance of breast cancer. 1 Current NCCN guidelines state that routine use of tumor markers in asymptomatic patients provides no survival advantage and is not recommended. 1

Serum tumor markers may have limited utility in:

• Monitoring response to therapy in metastatic disease (though imaging is preferred)
• Detecting recurrence in patients with previously elevated markers (though clinical examination and imaging are more reliable)

Management of Locally Advanced HER2-Positive Breast Cancer

Rationale for Neoadjuvant Therapy

Neoadjuvant systemic therapy has become the standard approach for locally advanced breast cancer (stage IIB-III), offering multiple advantages over adjuvant therapy administered after surgery. 1

Advantages of Neoadjuvant Therapy:

1. Tumor Downstaging: Neoadjuvant chemotherapy can reduce tumor size and convert inoperable tumors to operable status, or enable breast-conserving surgery in patients who would otherwise require mastectomy. 1 In this case, the patient achieved 63% reduction in tumor size (5.4 cm to 2.0 cm) and complete resolution of axillary lymphadenopathy, facilitating surgical resection.

2. In Vivo Assessment of Treatment Response: Neoadjuvant therapy allows real-time evaluation of tumor biology and treatment sensitivity, providing prognostic information. Patients achieving pathological complete response (pCR) have significantly improved disease-free survival and overall survival compared to those with residual disease. 1, 2

3. Early Treatment of Micrometastatic Disease: Systemic therapy is initiated earlier in the disease course, potentially eradicating micrometastases before they become clinically apparent.

4. Facilitation of Clinical Research: The neoadjuvant setting provides an ideal platform for evaluating novel therapeutic agents and biomarkers, with pCR serving as a surrogate endpoint for long-term outcomes.

Disadvantages and Considerations:

1. Loss of Pathological Staging Information: Neoadjuvant therapy alters the tumor and lymph node architecture, making accurate pathological staging more challenging. Pre-treatment clinical staging must be carefully documented.

2. Potential for Disease Progression: In patients with chemotherapy-resistant disease, neoadjuvant therapy may delay definitive surgical treatment, though this risk is mitigated by regular clinical and radiological assessment during treatment.

3. Surgical Planning Challenges: Accurate localization of the original tumor bed may be difficult after significant tumor response, necessitating placement of surgical clips prior to neoadjuvant therapy.

For this patient with clinical stage IIIA disease (cT3N1M0), neoadjuvant chemotherapy was the appropriate treatment approach, consistent with NCCN guidelines recommending neoadjuvant therapy for patients with clinical stage T2 or greater, or node-positive HER2-positive breast cancer. 1

Neoadjuvant Chemotherapy Regimens for HER2-Positive Disease

The standard neoadjuvant chemotherapy regimen for HER2-positive breast cancer consists of anthracycline-based therapy followed by taxane-based therapy with concurrent HER2-targeted therapy (trastuzumab with or without pertuzumab). 1

This Patient's Regimen:

• Phase 1: Doxorubicin and cyclophosphamide (AC) every 21 days x 4 cycles
• Phase 2: Docetaxel 100 mg/m² plus trastuzumab 300 mg every 21 days x 4 cycles
• Total duration: 8 cycles over approximately 6 months

Evidence Supporting This Approach:

NSABP B-27 Trial: This landmark trial demonstrated that adding docetaxel to AC chemotherapy in the neoadjuvant setting increased pathological complete response rates compared to AC alone, though it did not improve overall survival. 1 The trial established the AC followed by taxane sequential regimen as a standard backbone for neoadjuvant chemotherapy.

Incorporation of Trastuzumab: Multiple trials have demonstrated that adding trastuzumab to neoadjuvant chemotherapy in HER2-positive breast cancer significantly increases pathological complete response rates from 26% to 65.2%. 1 Key trials include:

• NOAH Trial: Demonstrated improved event-free survival with addition of trastuzumab to neoadjuvant chemotherapy in HER2-positive locally advanced breast cancer 1

• GeparQuattro Study: Showed pCR rate of 31.7% with trastuzumab plus anthracycline-taxane chemotherapy in HER2-positive tumors, compared to 15.7% in HER2-negative reference group 2

• GETN(A)-1 Trial: Reported 39% pCR rate with trastuzumab plus docetaxel and carboplatin in stage II/III HER2-positive breast cancer 6

Dual HER2 Blockade with Pertuzumab:

The addition of pertuzumab to trastuzumab and chemotherapy in the neoadjuvant setting has demonstrated further improvements in pathological complete response rates. 1

• NeoSphere Trial: Showed pCR rate of 45.8% with pertuzumab plus trastuzumab plus docetaxel vs. 29.0% with trastuzumab plus docetaxel alone 1

• TRYPHAENA Trial: Demonstrated pCR rates of 57-66% with pertuzumab plus trastuzumab plus chemotherapy (with or without anthracyclines) 1

• TRAIN-2 Trial: Showed similar pCR rates with anthracycline-containing (67%) vs. anthracycline-free (68%) regimens when combined with pertuzumab and trastuzumab, with less toxicity in the anthracycline-free arm 1

Current NCCN guidelines support the use of pertuzumab-containing regimens for neoadjuvant therapy in patients with HER2-positive breast cancer with tumors ≥T2 or ≥N1. 1 However, pertuzumab was not administered in this case, likely due to availability or cost considerations. Despite this, the patient achieved excellent tumor downstaging with trastuzumab-based therapy alone.

Alternative Regimens:

Anthracycline-Free Regimens: Based on TRAIN-2 results showing similar efficacy with less toxicity, anthracycline-free regimens such as docetaxel/carboplatin/trastuzumab/pertuzumab (TCH-P) are increasingly utilized, particularly in patients with cardiac risk factors. 1 However, the patient in this case received standard anthracycline-containing therapy without significant cardiac toxicity.

Dose-Dense Regimens: Dose-dense chemotherapy (administered every 2 weeks with growth factor support) has shown improved outcomes compared to conventional 3-week schedules in some studies, though this approach was not utilized in this case. 4

Cardiac Monitoring During HER2-Targeted Therapy

One of the most important safety considerations with trastuzumab-based therapy is the risk of cardiotoxicity, particularly when combined with anthracyclines. 1, 3 Trastuzumab-associated cardiac dysfunction is typically reversible and characterized by decreased left ventricular ejection fraction (LVEF) without structural myocardial damage (Type II cardiotoxicity), in contrast to anthracycline-induced irreversible cardiomyopathy (Type I cardiotoxicity).

Cardiac Monitoring Requirements:

Pre-treatment Assessment:

• Baseline LVEF measurement by echocardiography or MUGA scan
• Baseline LVEF must be ≥50% to initiate trastuzumab therapy 3
• Assessment of cardiac risk factors (hypertension, diabetes, prior anthracycline exposure, chest radiation)

During Treatment:

• LVEF assessment every 3 months during trastuzumab therapy per FDA label recommendations 3
• More frequent monitoring if LVEF decline is detected or cardiac symptoms develop

Management of LVEF Decline:

Asymptomatic LVEF Decline:

• LVEF decrease ≥10 percentage points from baseline to <50%: Withhold trastuzumab and repeat LVEF in 4 weeks
• If LVEF returns to normal limits and absolute decrease from baseline is ≤15 percentage points: Resume trastuzumab
• If LVEF remains <50% or absolute decrease from baseline is >15 percentage points: Strongly consider permanent discontinuation 3

Symptomatic Heart Failure:

• Discontinue trastuzumab permanently
• Initiate heart failure management with ACE inhibitors, beta-blockers, and diuretics as appropriate

In this case, the patient underwent appropriate cardiac monitoring throughout neoadjuvant therapy with no documented clinically significant cardiac dysfunction, demonstrating the safety of trastuzumab when administered with proper surveillance. 1, 3

Assessment of Treatment Response

Regular assessment of tumor response during neoadjuvant therapy is essential to ensure treatment efficacy and allow for regimen modification if disease progression occurs. 1

Methods of Response Assessment:

1. Clinical Examination: Serial physical examination to assess changes in tumor size, skin involvement, and axillary lymphadenopathy

2. Imaging Studies:

   • Ultrasound: Most commonly used modality for monitoring response, as utilized in this case
   • Mammography: May be performed mid-treatment or pre-operatively
   • MRI: Most accurate for assessing extent of residual disease but not routinely required

3. Timing of Assessment:

   • After completion of anthracycline phase (4 cycles AC)
   • After completion of all neoadjuvant therapy (prior to surgery)
   • Additional interim assessments if clinical concern for disease progression

In this patient, post-neoadjuvant ultrasound demonstrated excellent response with 63% reduction in tumor size (5.4 cm to 2.0 cm) and complete resolution of axillary lymphadenopathy, indicating significant treatment sensitivity. 1, 2

Surgical Management: Modified Radical Mastectomy vs. Breast-Conserving Therapy

Following completion of neoadjuvant chemotherapy, patients with locally advanced breast cancer who achieve adequate tumor response may be candidates for either breast-conserving therapy (lumpectomy plus radiation) or mastectomy. 1

Breast-Conserving Therapy After Neoadjuvant Chemotherapy

Breast-conserving therapy (BCT) consists of lumpectomy with negative margins followed by whole-breast radiation therapy, with or without regional nodal irradiation. 1 Multiple trials have demonstrated that neoadjuvant chemotherapy increases breast conservation rates compared to upfront surgery.

NSABP B-18 Trial: This landmark trial showed that breast conservation rates were higher after preoperative chemotherapy compared to postoperative adjuvant chemotherapy, though there was no difference in disease-specific survival between the two approaches. 1 This established neoadjuvant chemotherapy as a strategy to facilitate breast conservation in patients who would otherwise require mastectomy.

Requirements for Breast-Conserving Therapy:

• Ability to achieve negative surgical margins (no tumor on ink)
• Acceptable cosmetic outcome anticipated
• Absence of extensive suspicious microcalcifications
• Patient willingness to undergo radiation therapy
• No contraindications to radiation (prior chest radiation, pregnancy, connective tissue disorders)

In this case, the patient was initially scheduled for breast-conserving surgery following excellent tumor response to neoadjuvant therapy (tumor reduction from 5.4 cm to 2.0 cm). 1 However, the patient ultimately opted for modified radical mastectomy after informed discussion of surgical options, likely influenced by desire to minimize local recurrence risk and avoid radiation therapy.

Modified Radical Mastectomy

Modified radical mastectomy involves complete removal of the breast tissue (including nipple-areolar complex) with level I and II axillary lymph node dissection, while preserving the pectoralis major and minor muscles. 1

Indications for Mastectomy:

• Patient preference (as in this case)
• Inability to achieve negative margins with breast-conserving surgery
• Contraindications to radiation therapy
• Multicentric disease (tumors in different quadrants)
• Extensive suspicious microcalcifications
• Unfavorable tumor-to-breast size ratio precluding acceptable cosmetic outcome

Advantages of Mastectomy:

• Lower local recurrence rates compared to breast-conserving therapy (approximately 5-10% vs. 10-15% at 10 years)
• Elimination of need for radiation therapy in selected patients (though post-mastectomy radiation is still indicated for locally advanced disease)
• Single definitive surgical procedure

Disadvantages of Mastectomy:

• Loss of breast with associated psychological impact
• More extensive surgery with longer recovery
• Potential for chronic pain syndromes and lymphedema
• Need for reconstruction if desired (immediate or delayed)

In this patient, modified radical mastectomy was performed successfully with no intraoperative complications, negative surgical margins, and complete pathological nodal response (ypN0). 1 The decision for mastectomy over breast-conserving therapy was appropriate given patient preference and the initial locally advanced presentation.

Axillary Management After Neoadjuvant Chemotherapy

Management of the axilla in patients receiving neoadjuvant chemotherapy for node-positive disease remains an area of active investigation and evolving practice. 1

Pre-Neoadjuvant Axillary Assessment:

This patient underwent fine needle aspiration (FNA) of suspicious axillary lymph nodes prior to neoadjuvant therapy, which yielded a false-negative result (no malignant cells identified despite clinical and radiological suspicion for nodal involvement). 1 This highlights a limitation of FNA, which has lower sensitivity compared to core needle biopsy for detecting nodal metastases.

Current recommendations favor ultrasound-guided core needle biopsy over FNA for pathological confirmation of axillary nodal involvement in patients with suspicious lymph nodes on imaging. 1 Core biopsy provides tissue architecture assessment and has higher sensitivity (approximately 85-95%) compared to FNA (approximately 60-80%).

Axillary Surgery After Neoadjuvant Chemotherapy:

For patients with clinically node-positive disease at presentation who receive neoadjuvant chemotherapy, the standard approach is axillary lymph node dissection (ALND) at the time of definitive surgery, as performed in this patient. 1

Sentinel Lymph Node Biopsy (SLNB) After Neoadjuvant Chemotherapy:

The role of SLNB in patients with node-positive disease at presentation who achieve complete nodal response to neoadjuvant chemotherapy is evolving. Several trials have evaluated the accuracy of SLNB in this setting:

• ACOSOG Z1071 Trial: Showed false-negative rate of 12.6% for SLNB after neoadjuvant chemotherapy in initially node-positive patients, which decreased to 9.1% when ≥3 sentinel nodes were removed and dual tracer technique was used

• SENTINA Trial: Demonstrated false-negative rate of 14.2% for SLNB after neoadjuvant chemotherapy in initially node-positive patients

Based on these data, SLNB after neoadjuvant chemotherapy in initially node-positive patients is considered acceptable if:

• Dual tracer technique is used (radioisotope plus blue dye)
• ≥3 sentinel lymph nodes are identified and removed
• Patients are counseled regarding false-negative rate of approximately 10%

However, many surgeons and institutions continue to perform ALND in initially node-positive patients regardless of response to neoadjuvant therapy, as was done in this case. 1 This approach ensures complete pathological staging and minimizes risk of leaving residual nodal disease.

In this patient, ALND revealed complete pathological nodal response (ypN0), indicating excellent treatment sensitivity and favorable prognosis. 1, 2 The number of lymph nodes examined was not specified in the available records but should ideally be ≥10 nodes for adequate staging.

Pathological Response and Prognostic Implications

Pathological complete response (pCR) is defined as the absence of invasive carcinoma in the breast and axillary lymph nodes at the time of definitive surgery following neoadjuvant therapy. 1, 2 Some definitions also require absence of ductal carcinoma in situ (ypT0/is ypN0), while others accept residual DCIS (ypT0 ypN0).

This patient achieved substantial tumor downstaging with residual 2.0 cm invasive carcinoma in the breast (ypT2) but complete pathological nodal response (ypN0), representing an excellent but not complete pathological response. 1, 2

Pathological Complete Response Rates in HER2-Positive Disease

Expected pCR rates in HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab range from 30-50%, with higher rates observed when pertuzumab is added (50-67%). 1, 2

Factors Associated with Higher pCR Rates:

• HER2-positive/hormone receptor-negative subtype (pCR rates 50-70%)
• High tumor grade and Ki-67 proliferation index
• Smaller initial tumor size
• Addition of pertuzumab to trastuzumab-based regimens
• Younger age

Factors Associated with Lower pCR Rates:

• HER2-positive/hormone receptor-positive subtype (pCR rates 20-40%), as in this patient 1, 2
• Lower tumor grade
• Larger initial tumor size (>5 cm)
• Extensive nodal involvement

This patient's hormone receptor-positive status likely contributed to the lack of complete pathological response, as ER/PR-positive tumors are generally less chemosensitive than hormone receptor-negative tumors. 1, 2 However, the achievement of complete nodal response (ypN0) is highly favorable and associated with improved outcomes.

Prognostic Significance of Pathological Response

Multiple studies have demonstrated that achievement of pCR following neoadjuvant chemotherapy is associated with significantly improved disease-free survival and overall survival compared to patients with residual disease. 1, 2

Meta-analyses have shown:

• Patients achieving pCR have approximately 50-60% reduction in risk of recurrence compared to those with residual disease
• The prognostic value of pCR is strongest in aggressive subtypes (triple-negative and HER2-positive/hormone receptor-negative)
• In HER2-positive/hormone receptor-positive disease (as in this patient), the prognostic value of pCR is less pronounced but still significant

Residual Cancer Burden (RCB):

An alternative method for quantifying pathological response is the Residual Cancer Burden (RCB) score, which incorporates:

• Dimensions of primary tumor bed
• Proportion of tumor bed containing invasive carcinoma
• Number of positive lymph nodes
• Diameter of largest nodal metastasis

RCB is classified as:

• RCB-0: pCR (no residual invasive disease)
• RCB-I: Minimal residual disease
• RCB-II: Moderate residual disease
• RCB-III: Extensive residual disease

This patient would likely be classified as RCB-II (moderate residual disease) given the 2.0 cm residual tumor in the breast with complete nodal response, which is associated with intermediate prognosis. 1

Five-Year Outcomes:

Based on published data from similar patient populations:

• Disease-Free Survival: Approximately 70-80% at 5 years for HER2-positive/hormone receptor-positive patients achieving partial response to neoadjuvant therapy 7

• Overall Survival: Approximately 80-90% at 5 years for HER2-positive/hormone receptor-positive patients with residual disease after neoadjuvant therapy 7

The complete pathological nodal response (ypN0) in this patient is particularly favorable and suggests excellent treatment sensitivity, likely translating to improved long-term outcomes. 1, 2

Adjuvant Therapy Following Neoadjuvant Chemotherapy and Surgery

Following completion of neoadjuvant chemotherapy and definitive surgery, patients require additional adjuvant therapy based on tumor characteristics and pathological response. 1, 4

Completion of HER2-Targeted Therapy

This patient received 4 cycles of trastuzumab during the neoadjuvant phase (concurrent with docetaxel) and requires completion of a total of 1 year (52 weeks) of trastuzumab therapy in the adjuvant setting. 1, 3

Standard Trastuzumab Duration:

• Total duration: 1 year (52 weeks) of trastuzumab therapy 1, 3
• Administered as 6 mg/kg intravenously every 3 weeks (or 2 mg/kg weekly) following completion of chemotherapy
• Continue until 1 year from initiation of trastuzumab (including neoadjuvant portion)

Evidence for 1-Year Duration:

HERA Trial: This landmark trial compared 1 year vs. 2 years of adjuvant trastuzumab vs. observation in HER2-positive early breast cancer. Results showed:

• Significant improvement in disease-free survival with 1 year of trastuzumab vs. observation (HR 0.76,95% CI 0.67-0.86)
• No additional benefit with 2 years vs. 1 year of trastuzumab (HR 0.99,95% CI 0.87-1.13) 3
• Increased cardiac toxicity with longer duration of therapy

Shorter Duration Trials:

PERSEPHONE Trial: Demonstrated non-inferiority of 6 months vs. 12 months of trastuzumab, though this remains controversial 1

PHARE Trial: Failed to demonstrate non-inferiority of 6 months vs. 12 months of trastuzumab 1

Given the conflicting results and the established efficacy of 12 months of therapy in multiple randomized trials, the NCCN panel recommends up to 1 year of HER2-targeted therapy with trastuzumab. 1

Cardiac Monitoring During Adjuvant Trastuzumab:

• Continue LVEF assessments every 3 months during trastuzumab therapy 3
• Withhold trastuzumab for asymptomatic LVEF decline as outlined previously
• Permanently discontinue for symptomatic heart failure

Adjuvant Endocrine Therapy

This patient's tumor is ER-positive (60%) and PR-positive (60%), making her a candidate for extended adjuvant endocrine therapy for 5-10 years. 1, 4

Endocrine Therapy Options for Premenopausal Women:

Option 1: Ovarian Function Suppression (OFS) Plus Aromatase Inhibitor (Preferred for High-Risk Disease)

• LHRH agonist (goserelin 3.6 mg subcutaneously every 28 days or leuprolide 3.75 mg intramuscularly every 28 days) PLUS
• Aromatase inhibitor (letrozole 2.5 mg daily, anastrozole 1 mg daily, or exemestane 25 mg daily)
• Duration: 5 years, with consideration of extended therapy to 10 years for high-risk features 4

Evidence: SOFT and TEXT trials demonstrated superior disease-free survival with OFS plus AI compared to tamoxifen alone in premenopausal women with high-risk hormone receptor-positive breast cancer 4

Option 2: Tamoxifen With or Without OFS

• Tamoxifen 20 mg daily for 5-10 years
• May add OFS for additional benefit in high-risk patients
• Less preferred than OFS plus AI for patients with initial stage III disease 4

For this patient with initial stage IIIA disease, young age (35 years), and high Ki-67 proliferation index, ovarian function suppression plus aromatase inhibitor is the preferred endocrine therapy approach. 4

Important Considerations:

1. Timing: Endocrine therapy should be initiated after completion of chemotherapy and can be administered concurrently with trastuzumab and radiation therapy 1

2. Monitoring:

   • Assess menopausal status periodically, as chemotherapy-induced amenorrhea may be temporary
   • If aromatase inhibitor is used, confirm adequate estrogen suppression with serum estradiol and FSH/LH levels
   • Monitor bone density with DEXA scans every 1-2 years due to increased osteoporosis risk with AI therapy

3. Duration:

   • Minimum 5 years of endocrine therapy
   • Consider extended therapy to 10 years for high-risk features (initial stage III, young age, high grade)

4. Side Effects:

   • OFS: Hot flashes, vaginal dryness, decreased libido, mood changes
   • AI: Arthralgias, myalgias, bone loss, cardiovascular effects
   • Tamoxifen: Hot flashes, thromboembolic events, endometrial hyperplasia

Post-Mastectomy Radiation Therapy

Post-mastectomy radiation therapy (PMRT) is indicated for patients with locally advanced breast cancer to reduce risk of locoregional recurrence. 1

Indications for PMRT:

• Initial clinical stage III disease (as in this patient with cT3N1M0) 1
• Pathological T3 or T4 tumors
• ≥4 positive axillary lymph nodes
• Positive surgical margins

Radiation Fields:

• Chest wall (entire mastectomy scar and surgical bed)
• Supraclavicular lymph nodes
• Strong consideration for inclusion of internal mammary lymph nodes (category 2B recommendation) 1
• Axillary apex if indicated

Timing:

• Initiate after completion of chemotherapy (if not completed preoperatively)
• Can be administered concurrently with trastuzumab and endocrine therapy 1
• Typically begins 4-6 weeks after surgery once surgical wounds are healed

Dose and Fractionation:

• Standard: 50 Gy in 25 fractions over 5 weeks
• Hypofractionated: 40-42.5 Gy in 15-16 fractions over 3-3.5 weeks (increasingly utilized)
• Boost to tumor bed or high-risk areas: Additional 10-16 Gy if indicated

For this patient with initial clinical stage IIIA disease, post-mastectomy radiation therapy to the chest wall and regional lymph nodes is strongly recommended to minimize locoregional recurrence risk. 1

Consideration of Adjuvant Capecitabine

The CREATE-X trial demonstrated benefit of adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy, particularly in triple-negative and HER2-positive disease. 1 However, this approach remains controversial and is not universally adopted.

For this patient with HER2-positive/hormone receptor-positive disease and residual 2.0 cm tumor after neoadjuvant therapy, adjuvant capecitabine could be considered but is not standard of care. 1 The decision should be individualized based on risk-benefit assessment and patient preference.

Post-Treatment Surveillance and Follow-Up

Following completion of all adjuvant therapy, patients require long-term surveillance for detection of recurrence and management of treatment-related late effects. 1

Surveillance Schedule

Clinical Examination:

• Every 3-4 months for years 1-3
• Every 6 months for years 4-5
• Annually after year 5
• Focus on detection of locoregional recurrence, contralateral breast cancer, and symptoms of distant metastases

Imaging:

• Mammography: Annual mammography of contralateral breast (ipsilateral breast if breast-conserving therapy performed) 1
• First post-treatment mammogram: 6-12 months after completion of radiation therapy if breast-conserving therapy performed
• Breast MRI: Consider for high-risk patients (BRCA mutation carriers, strong family history) for enhanced surveillance

Laboratory and Imaging Studies:

• Routine tumor markers (CA 15-3, CA 27.29, CEA): NOT recommended for surveillance in asymptomatic patients 1
• Routine imaging (CT, bone scan, PET): NOT recommended for surveillance in asymptomatic patients 1
• Imaging should be performed only if symptoms or physical examination findings suggest recurrence

Cardiac Surveillance:

• Continue periodic LVEF assessments for at least 2 years after completion of trastuzumab
• More frequent monitoring if any cardiac dysfunction detected during treatment

Bone Health:

• DEXA scans every 1-2 years for patients on aromatase inhibitor therapy
• Calcium and vitamin D supplementation
• Bisphosphonates or denosumab if osteoporosis develops

Management of Treatment-Related Late Effects

Lymphedema:

• Patient education regarding arm precautions (avoid blood pressure measurements, venipuncture, trauma to affected arm)
• Early referral to lymphedema specialist if swelling develops
• Compression garments and manual lymphatic drainage as needed

Neuropathy:

• Persistent peripheral neuropathy from taxane chemotherapy may occur
• Symptomatic management with gabapentin, pregabalin, or duloxetine
• Physical therapy and occupational therapy as needed

Menopausal Symptoms:

• Non-hormonal management of hot flashes (venlafaxine, paroxetine, gabapentin)
• Vaginal moisturizers and lubricants for vaginal dryness
• Avoid systemic hormone replacement therapy due to breast cancer history

Psychosocial Support:

• Screening for depression and anxiety
• Referral to support groups and counseling services
• Body image counseling, particularly after mastectomy

Special Considerations in Young Women with Breast Cancer

This patient's young age at diagnosis (35 years) raises several important considerations that impact treatment decisions and long-term management. 1

Fertility Preservation

Chemotherapy, particularly alkylating agents like cyclophosphamide, can cause premature ovarian failure and infertility in premenopausal women. The risk of chemotherapy-induced amenorrhea increases with age and cumulative dose of alkylating agents.

Fertility Preservation Options:

• Embryo cryopreservation (most established method, requires partner or donor sperm)
• Oocyte cryopreservation (does not require partner)
• Ovarian tissue cryopreservation (experimental, may be option for prepubertal patients)
• Ovarian suppression with LHRH agonists during chemotherapy (controversial efficacy)

In this patient, fertility preservation options should have been discussed prior to initiation of neoadjuvant chemotherapy. 1 Given her nulligravid status and young age, preservation of fertility potential may have been an important consideration. However, the medical records do not document whether fertility preservation counseling was provided or pursued.

Future Pregnancy Considerations:

• Pregnancy is generally considered safe after completion of treatment and appropriate disease-free interval (typically 2-3 years)
• Temporary interruption of endocrine therapy may be considered for pregnancy attempt after 2-3 years of therapy, with resumption after delivery and lactation
• Pregnancy does not appear to adversely affect breast cancer outcomes in hormone receptor-positive disease

Genetic Testing and Hereditary Cancer Syndromes

This patient's young age at diagnosis and paternal family history of breast cancer raise concern for hereditary breast cancer syndrome, particularly BRCA1 or BRCA2 mutation. 1

Indications for Genetic Testing:

• Breast cancer diagnosis before age 50 (particularly before age 45)
• Triple-negative breast cancer before age 60
• Bilateral breast cancer
• Breast cancer and ovarian cancer in same individual
• Male breast cancer
• Ashkenazi Jewish ancestry
• Family history of breast, ovarian, pancreatic, or prostate cancer

This patient meets criteria for genetic testing based on young age at diagnosis and family history. 1 Genetic counseling and testing for BRCA1/BRCA2 and other hereditary cancer genes should be offered.

Implications of BRCA Mutation:

If BRCA Mutation Identified:

• Consideration of bilateral mastectomy (contralateral prophylactic mastectomy) to reduce risk of contralateral breast cancer (30-40% lifetime risk in BRCA carriers) 1
• Consideration of risk-reducing bilateral salpingo-oophorectomy after completion of childbearing to reduce ovarian cancer risk (20-40% lifetime risk in BRCA1 carriers, 10-20% in BRCA2 carriers) 1
• Eligibility for PARP inhibitor therapy (olaparib) in adjuvant setting for high-risk disease 4
• Enhanced surveillance with annual breast MRI in addition to mammography
• Cascade testing of family members

In this case, the patient underwent unilateral modified radical mastectomy, but if BRCA mutation is identified, discussion of contralateral prophylactic mastectomy should be undertaken. 1

Psychosocial Impact

Young women with breast cancer face unique psychosocial challenges including:

• Body image concerns, particularly after mastectomy
• Sexual dysfunction related to treatment-induced menopause and vaginal dryness
• Fertility concerns and grief over potential loss of childbearing capacity
• Career and financial impact of prolonged treatment
• Concerns about genetic risk to children
• Social isolation from peers who may not understand cancer experience

Comprehensive psychosocial support, including counseling, support groups, and survivorship programs, should be integral components of care for young women with breast cancer. 1

Literature Review: Recent Advances in Neoadjuvant Therapy for HER2-Positive Breast Cancer

Dual HER2 Blockade with Pertuzumab

The addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy represents one of the most significant recent advances in treatment of HER2-positive breast cancer. 1

Mechanism of Action: Pertuzumab and trastuzumab bind to different epitopes on the HER2 receptor, providing complementary mechanisms of action:

• Trastuzumab binds to domain IV of HER2, preventing receptor cleavage and inducing antibody-dependent cellular cytotoxicity
• Pertuzumab binds to domain II of HER2, preventing heterodimerization with other HER family receptors (particularly HER3)

Key Clinical Trials:

NeoSphere Trial:

• Randomized phase II trial comparing four neoadjuvant regimens in HER2-positive breast cancer
• pCR rates: Pertuzumab + trastuzumab + docetaxel (45.8%) vs. trastuzumab + docetaxel (29.0%) 1
• Demonstrated significant improvement in pCR with dual HER2 blockade

TRYPHAENA Trial:

• Evaluated safety and efficacy of pertuzumab plus trastuzumab with anthracycline-containing or anthracycline-free chemotherapy
• pCR rates ranged from 57-66% across treatment arms 1
• Demonstrated acceptable cardiac safety profile with dual HER2 blockade

TRAIN-2 Trial:

• Compared anthracycline-containing vs. anthracycline-free regimens with pertuzumab and trastuzumab
• Similar pCR rates: Anthracycline-containing (67%) vs. anthracycline-free (68%) 1
• Less toxicity with anthracycline-free regimen (less febrile neutropenia, hypokalemia, and cardiac dysfunction) 1
• 3-year event-free survival and overall survival similar between arms

Current Recommendations:

• NCCN guidelines support pertuzumab-containing regimens for neoadjuvant therapy in HER2-positive breast cancer with tumors ≥T2 or ≥N1 1
• Both anthracycline-containing and anthracycline-free regimens are acceptable options
• Anthracycline-free regimens (docetaxel/carboplatin/trastuzumab/pertuzumab) may be preferred in patients with cardiac risk factors

Immunotherapy in Triple-Negative Breast Cancer

While not directly applicable to this HER2-positive case, the KEYNOTE-522 trial demonstrated significant benefit of adding pembrolizumab to neoadjuvant chemotherapy in triple-negative breast cancer. 1

KEYNOTE-522 Trial:

• Randomized phase III trial of neoadjuvant chemotherapy plus pembrolizumab vs. placebo in stage II-III triple-negative breast cancer
• Significant improvement in event-free survival: 3-year EFS 84.5% with pembrolizumab vs. 76.8% with placebo (HR 0.63, P <0.001) 1
• 5-year EFS: 81.3% with pembrolizumab vs. 72.3% with placebo 1
• Led to FDA approval of pembrolizumab in combination with chemotherapy for high-risk early-stage triple-negative breast cancer

This represents a paradigm shift in treatment of triple-negative breast cancer and highlights the importance of immunotherapy in breast cancer management. 1

Escalation and De-escalation Strategies

Recent research has focused on both escalation strategies for high-risk patients and de-escalation strategies for lower-risk patients to optimize treatment efficacy while minimizing toxicity.

Escalation Strategies:

KATHERINE Trial:

• Evaluated adjuvant trastuzumab emtansine (T-DM1) vs. trastuzumab in patients with residual disease after neoadjuvant chemotherapy plus trastuzumab
• Significant improvement in invasive disease-free survival with T-DM1 (HR 0.50,95% CI 0.39-0.64) 1
• Established T-DM1 as standard adjuvant therapy for patients with residual disease after neoadjuvant therapy

This patient, with residual 2.0 cm tumor after neoadjuvant therapy, would be a candidate for adjuvant T-DM1 instead of completing trastuzumab alone, based on KATHERINE trial results. 1 However, T-DM1 may not have been available or accessible at the time of treatment.

De-escalation Strategies:

APT Trial:

• Evaluated paclitaxel plus trastuzumab (without anthracycline) in small (≤3 cm), node-negative HER2-positive breast cancer
• Excellent 7-year disease-free survival of 93% and overall survival of 95% 8
• Established less intensive regimen as option for lower-risk HER2-positive disease

PHERGain Trial:

• Evaluated response-guided therapy with dual HER2 blockade
• Patients achieving early complete response after 2 cycles of pertuzumab, trastuzumab, and docetaxel omitted anthracyclines
• Demonstrated feasibility of de-escalation in patients with excellent early response

These trials highlight the importance of risk stratification and personalized treatment approaches in HER2-positive breast cancer. 1, 8

Novel HER2-Targeted Agents

Several novel HER2-targeted agents have been developed and are being evaluated in clinical trials:

Trastuzumab Deruxtecan (T-DXd):

• Antibody-drug conjugate with more potent cytotoxic payload than T-DM1
• Demonstrated superior efficacy compared to T-DM1 in metastatic HER2-positive breast cancer (DESTINY-Breast03 trial)
• Being evaluated in neoadjuvant and adjuvant settings

Tucatinib:

• Oral tyrosine kinase inhibitor with high selectivity for HER2
• Demonstrated efficacy in combination with trastuzumab and capecitabine in metastatic HER2-positive breast cancer, including brain metastases (HER2CLIMB trial)
• Being evaluated in earlier disease settings

Margetuximab:

• Fc-engineered anti-HER2 antibody with enhanced immune effector function
• Demonstrated modest benefit over trastuzumab in metastatic disease (SOPHIA trial)

These novel agents represent the next generation of HER2-targeted therapies and may further improve outcomes in HER2-positive breast cancer. 1

Conclusion

This case demonstrates the efficacy of neoadjuvant chemotherapy with anthracycline-taxane regimen plus trastuzumab in achieving substantial tumor downstaging in locally advanced HER2-positive breast cancer, with reduction from clinical stage IIIA (cT3N1M0) to pathological stage IIA (ypT2N0M0) and complete nodal response. 1, 2 The patient's excellent response to neoadjuvant therapy, with 63% reduction in primary tumor size and resolution of axillary lymphadenopathy, facilitated successful surgical resection with modified radical mastectomy and portends favorable long-term prognosis.

Key learning points from this case include:

1. The critical importance of timely diagnosis and adherence to surveillance recommendations: The patient's 18-month delay in follow-up after initial BI-RADS III classification resulted in disease progression from potentially early-stage to locally advanced presentation, highlighting the need for robust patient tracking systems and education. 1

2. The value of comprehensive staging with clinical examination, imaging (ultrasound, CT, bone scan), and tissue diagnosis (core needle biopsy with immunohistochemistry and FISH) in guiding treatment decisions: Accurate pre-treatment staging is essential for appropriate treatment selection and prognostic assessment. 1

3. The efficacy of neoadjuvant chemotherapy plus trastuzumab in HER2-positive breast cancer: Standard anthracycline-taxane sequential regimens combined with HER2-targeted therapy achieve pathological complete response rates of 30-50% and substantial tumor downstaging in the majority of patients. 1, 2

4. The importance of cardiac monitoring during trastuzumab-based therapy: Serial LVEF assessments are essential to detect and manage cardiac dysfunction, which is typically reversible if identified early. 1, 3

5. The prognostic significance of pathological response: Complete pathological nodal response (ypN0), as achieved in this patient, is associated with improved disease-free survival and overall survival, even in the absence of complete pathological response in the breast. 1, 2

6. The need for comprehensive adjuvant therapy: Following neoadjuvant chemotherapy and surgery, patients require completion of 1 year of trastuzumab, extended endocrine therapy (5-10 years), and post-mastectomy radiation therapy to optimize long-term outcomes. 1, 4

7. Special considerations in young women with breast cancer: Young age at diagnosis necessitates discussion of fertility preservation, genetic testing for hereditary cancer syndromes, and comprehensive psychosocial support. 1

This patient's favorable response to neoadjuvant therapy and achievement of complete nodal response suggest excellent treatment sensitivity and favorable prognosis, with expected 5-year disease-free survival of approximately 70-80% and overall survival of 80-90%. 7 Continued adherence to adjuvant therapy (completion of trastuzumab, extended endocrine therapy, radiation therapy) and long-term surveillance will be essential to optimize outcomes and detect any recurrence at the earliest possible stage.

The case also highlights areas for potential improvement in management, including consideration of pertuzumab addition to neoadjuvant regimen (if available and accessible), genetic testing for BRCA mutations given young age and family history, and potential use of adjuvant trastuzumab emtansine (T-DM1) instead of trastuzumab alone given residual disease after neoadjuvant therapy. 1 These considerations should be discussed with the patient as part of shared decision-making regarding optimal treatment strategy.

References

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