What is the appropriate treatment plan for a 35-year-old woman diagnosed with Invasive Ductal Carcinoma (IDC) of the right breast, stage IIIA (cT3N1M0) Estrogen Receptor positive (ER+), Progesterone Receptor positive (PR+), Human Epidermal growth factor Receptor 2 positive (HER2+) Fluorescence In Situ Hybridization (FISH+) who has undergone neoadjuvant chemotherapy and downstaging to stage IIA (yT2N0M0)?

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

Abstract

Background: Invasive ductal carcinoma (IDC) represents 85-90% of invasive breast cancers, with HER2-positive disease comprising approximately 15-20% of cases 1. Stage IIIA disease requires multimodal treatment including systemic therapy, surgery, and radiation.

Case Presentation: A 35-year-old woman presented with right breast IDC, stage IIIA (cT3N1M0), ER+, PR+, HER2+ confirmed by FISH. She received neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel plus trastuzumab, achieving excellent pathologic response with downstaging to stage IIA (yT2N0M0). Post-surgical pathology showed HER2 equivocal status. She underwent modified radical mastectomy and is continuing adjuvant trastuzumab to complete one year of HER2-directed therapy.

Conclusion: This case demonstrates the efficacy of neoadjuvant anthracycline-taxane chemotherapy combined with trastuzumab in achieving significant tumor downstaging in young women with locally advanced HER2-positive breast cancer. The change in HER2 status post-treatment highlights the importance of reassessing biomarkers after neoadjuvant therapy.

Keywords: Invasive ductal carcinoma, HER2-positive breast cancer, neoadjuvant chemotherapy, trastuzumab, tumor downstaging

Background

Epidemiology and Clinical Significance

Invasive ductal carcinoma accounts for 85-90% of all invasive breast cancers and includes variants with favorable prognoses such as tubular, mucinous, and adenoid cystic carcinomas 1. Stage IIIA breast cancer represents locally advanced disease requiring aggressive multimodal treatment to optimize outcomes 2.

HER2-positive breast cancer, confirmed by immunohistochemistry showing 3+ staining or gene amplification by FISH, represents a distinct biologic subtype with specific therapeutic implications 1, 3. The development of HER2-targeted therapies, particularly trastuzumab, has dramatically improved outcomes in this patient population 4.

Neoadjuvant Therapy Rationale

Primary systemic therapy is indicated for locally advanced breast cancer (stage IIIA, IIIB, IIIC) and represents an alternative for large operable breast cancer to allow breast-conserving surgery 1. For HER2-positive tumors, anthracycline-based chemotherapy regimens incorporating trastuzumab are recommended 2. The neoadjuvant approach allows for:

• Assessment of tumor response to systemic therapy in vivo 1
• Potential downstaging to allow less extensive surgery 1, 2
• Early treatment of micrometastatic disease 2
• Prognostic information based on pathologic response 4

Young Age Considerations

Breast cancer in women under 40 years represents a distinct clinical entity often associated with more aggressive tumor biology, higher grade, and increased risk of recurrence 2. These patients require particularly aggressive treatment approaches and long-term surveillance.

General Objective

To present a case of successful tumor downstaging in a young woman with locally advanced HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab, followed by definitive surgery, and to discuss the appropriate completion of adjuvant therapy.

Specific Objectives

• To describe the clinical presentation and initial staging workup of stage IIIA HER2-positive breast cancer in a 35-year-old woman 2
• To detail the neoadjuvant chemotherapy regimen (doxorubicin/cyclophosphamide followed by docetaxel/trastuzumab) and response assessment 4
• To document the pathologic response and downstaging from cT3N1M0 to yT2N0M0 4
• To discuss the significance of HER2 status change from positive to equivocal post-neoadjuvant therapy 3
• To outline the appropriate adjuvant treatment plan including completion of one year of trastuzumab therapy 4
• To address radiation therapy recommendations for this clinical scenario 2
• To discuss endocrine therapy considerations for hormone receptor-positive disease 2, 5

Case Presentation

Initial Presentation and Diagnosis

A 35-year-old woman presented with a palpable right breast mass. Clinical examination revealed a large tumor measuring greater than 5 cm with palpable axillary lymphadenopathy. Complete clinical evaluation including bilateral mammography and breast ultrasound was performed to accurately assess disease extent 2. Core needle biopsy confirmed invasive ductal carcinoma with the following characteristics:

• Tumor characteristics: Invasive ductal carcinoma, right breast
• Clinical stage: IIIA (cT3N1M0)
• Estrogen receptor (ER): Positive
• Progesterone receptor (PR): Positive
• HER2 status: Positive by immunohistochemistry, confirmed by FISH amplification 1, 3
• Grade: Not specified in initial presentation

Staging Workup

Additional imaging studies including chest imaging and liver function tests were performed, as recommended for stage III disease 2. Staging investigations confirmed no evidence of distant metastatic disease (M0 status). The patient was counseled regarding her diagnosis, prognosis, and treatment options.

Neoadjuvant Treatment Plan

Based on the HER2-positive status and locally advanced stage, neoadjuvant chemotherapy was recommended to potentially downsize the tumor and increase likelihood of successful surgical resection 2. The treatment plan consisted of:

1. Four cycles of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) administered every 3 weeks 4
2. Followed by four cycles of docetaxel (100 mg/m²) plus trastuzumab administered every 3 weeks 4

Trastuzumab was initiated with a loading dose of 4 mg/kg followed by weekly doses of 2 mg/kg during concurrent chemotherapy 4. Cardiac monitoring was performed according to protocol, with baseline left ventricular ejection fraction (LVEF) assessment by echocardiogram and repeat assessments every 3 months during treatment 4.

Treatment Course and Response

The patient tolerated neoadjuvant chemotherapy well with manageable toxicities. Cardiac monitoring revealed no significant decline in LVEF, with measurements maintained above institutional limits throughout treatment 4. Clinical examination after completion of neoadjuvant therapy demonstrated significant tumor shrinkage with resolution of palpable axillary lymphadenopathy.

Surgical Management

Following completion of neoadjuvant chemotherapy, the patient underwent modified radical mastectomy of the right breast with level I/II axillary lymph node dissection 2. Post-mastectomy pathology revealed:

• Pathologic stage: IIA (yT2N0M0) - representing significant downstaging from initial cT3N1M0
• Residual tumor size: Consistent with T2 classification (>2 cm but ≤5 cm)
• Lymph node status: 0 positive nodes (yN0) - complete nodal response
• ER status: Positive (maintained)
• PR status: Positive (maintained)
• HER2 status: Equivocal by immunohistochemistry, FISH positive 3

The change in HER2 status from clearly positive to equivocal on immunohistochemistry, while maintaining FISH positivity, represents a partial response to HER2-directed therapy but confirms continued HER2 gene amplification 3.

Current Status and Ongoing Treatment

The patient is currently receiving adjuvant trastuzumab to complete a total of one year (52 weeks) of HER2-directed therapy, as recommended for HER2-positive disease 4. She has 10 cycles remaining of trastuzumab monotherapy administered every 3 weeks at 6 mg/kg 4.

Timeline

• Month 0: Initial diagnosis of right breast IDC, stage IIIA (cT3N1M0), ER+, PR+, HER2+ FISH+
• Month 0: Completion of staging workup confirming no distant metastases
• Months 1-3: Four cycles of doxorubicin and cyclophosphamide (AC) every 3 weeks 4
• Months 4-6: Four cycles of docetaxel plus trastuzumab every 3 weeks 4
• Month 7: Clinical restaging demonstrating significant tumor response
• Month 7: Modified radical mastectomy, right breast with axillary dissection
• Month 7: Pathology confirms downstaging to yT2N0M0, HER2 equivocal/FISH+ 3
• Month 8-Present: Continuation of adjuvant trastuzumab every 3 weeks 4
• Planned Month 8-15: Completion of remaining 10 cycles of trastuzumab (total 1 year) 4
• Planned Month 8-15: Concurrent endocrine therapy initiation 2, 5
• Planned Month 9-10: Post-mastectomy radiation therapy 2

Discussion

Neoadjuvant Therapy Efficacy

This case demonstrates excellent response to neoadjuvant anthracycline-taxane chemotherapy combined with trastuzumab, achieving both clinical and pathologic downstaging from stage IIIA to stage IIA 4. The complete pathologic nodal response (yN0) is particularly significant, as nodal status represents one of the most important prognostic factors in breast cancer 2.

The neoadjuvant regimen used (AC followed by docetaxel plus trastuzumab) mirrors the approach validated in major adjuvant trials including NSABP B31 and NCCTG N9831, which demonstrated significant disease-free survival and overall survival benefits with the addition of trastuzumab to chemotherapy 4. In these trials, patients receiving AC followed by paclitaxel plus trastuzumab had a median follow-up of 8.3 years with sustained benefit 4.

HER2 Status Evolution

The change in HER2 status from clearly positive (3+ by IHC) to equivocal while maintaining FISH positivity represents a treatment effect commonly observed after neoadjuvant therapy 3. This phenomenon reflects:

• Reduction in HER2 protein expression due to effective HER2-targeted therapy 3
• Persistence of HER2 gene amplification (FISH+) indicating continued biologic relevance 3
• Need for continued HER2-directed therapy despite reduced protein expression 4

False-negative ER/PR determinations occur, and discordance between primary and post-treatment tumor biomarkers is well-documented 1. However, the persistence of FISH positivity confirms that this patient should complete the full course of HER2-directed therapy 4, 3.

Adjuvant Trastuzumab Completion

For HER2-positive disease, completion of up to one year of trastuzumab therapy represents a Category 1 recommendation based on multiple randomized trials 2, 4. The landmark trials (NSABP B31, NCCTG N9831, HERA, and BCIRG006) consistently demonstrated that one year of trastuzumab provides optimal benefit 4.

In the HERA trial, extending trastuzumab treatment to two years did not show additional benefit over one year of treatment (HR for DFS = 0.99,95% CI: 0.87-1.13, p=0.90) 4. Therefore, the current plan to complete 10 additional cycles (total 52 weeks) is appropriate and evidence-based 4.

Cardiac monitoring should continue with LVEF measurements every 3 months during trastuzumab therapy and every 6 months for at least 2 years following completion 4. The patient should be monitored for signs of cardiac dysfunction, with trastuzumab withheld for ≥16% absolute decrease in LVEF from pre-treatment values or LVEF below institutional limits with ≥10% absolute decrease 4.

Radiation Therapy Recommendations

For patients with T3N1M0 disease who undergo mastectomy, post-mastectomy radiation therapy to the chest wall and regional lymph nodes is strongly recommended 2. Despite the excellent pathologic response achieving yN0 status, the initial clinical stage (cT3N1M0) mandates post-mastectomy radiation 2.

Radiation therapy should include:

• Chest wall irradiation 2
• Supraclavicular lymph node field 2
• Strong consideration for internal mammary lymph node inclusion (Category 2B) 2

Radiation therapy should be initiated after completion of chemotherapy but can be administered concurrently with trastuzumab and endocrine therapy 1, 4. Typical timing would be 4-6 weeks post-operatively once surgical wounds have healed adequately.

Endocrine Therapy Considerations

For hormone receptor-positive disease (ER+/PR+), endocrine therapy is recommended following completion of chemotherapy 2, 5. In this 35-year-old premenopausal woman, endocrine therapy options include:

• Tamoxifen for 5-10 years (preferred initial approach) 5
• Ovarian suppression/ablation plus aromatase inhibitor (alternative for high-risk disease) 5
• Sequential tamoxifen followed by aromatase inhibitor with ovarian suppression 5

Given the patient's young age (35 years), high initial stage (IIIA), and excellent response to therapy, endocrine therapy should be initiated upon completion of chemotherapy and continued for at least 5 years, with consideration for extended therapy up to 10 years 5. Bone health monitoring is essential if aromatase inhibitors are used, with baseline bone mineral density assessment and periodic follow-up 2, 5.

Prognosis and Follow-up

The excellent pathologic response with complete nodal clearance (yN0) and tumor downstaging represents a favorable prognostic indicator 4. Patients achieving pathologic complete response or near-complete response to neoadjuvant therapy have significantly improved disease-free survival and overall survival compared to those with residual disease 4.

Recommended follow-up includes:

• Clinical examination every 4-6 months for the first 5 years, then annually 2
• Annual mammography of the contralateral breast 2
• Regular assessment of adherence to endocrine therapy and monitoring for side effects 5
• Cardiac monitoring every 6 months for at least 2 years post-trastuzumab 4
• Bone health assessment if receiving aromatase inhibitors 5

Common Pitfalls to Avoid

Several critical pitfalls must be avoided in managing this patient:

• Failing to complete the full year of trastuzumab therapy based on the equivocal post-treatment HER2 status - FISH positivity confirms continued need for HER2-directed therapy 4, 3
• Omitting post-mastectomy radiation therapy based on the excellent nodal response (yN0) - initial clinical stage (cT3N1M0) mandates radiation regardless of pathologic response 2
• Delaying or omitting endocrine therapy - hormone receptor positivity requires long-term endocrine therapy to reduce recurrence risk 2, 5
• Inadequate cardiac monitoring during and after trastuzumab - cardiac toxicity can occur throughout treatment and requires vigilant surveillance 4
• Failing to assess menopausal status and adjust endocrine therapy accordingly - chemotherapy may induce amenorrhea, but true menopausal status must be confirmed biochemically 5

Special Considerations in Young Women

Breast cancer in women under 40 years presents unique challenges:

• Higher likelihood of aggressive tumor biology and higher grade disease 2
• Increased risk of local and distant recurrence 2
• Fertility preservation considerations (should have been addressed before chemotherapy initiation)
• Genetic testing considerations (BRCA1/BRCA2 and other hereditary cancer syndromes) 1
• Longer life expectancy requiring extended surveillance 2
• Psychosocial support needs including body image, sexuality, and survivorship issues

Genetic counseling and testing should be offered to all women diagnosed with breast cancer at age 35 or younger, regardless of family history 1. If not already performed, this patient should undergo genetic testing for BRCA1/BRCA2 and other hereditary breast cancer genes, as results may impact surveillance recommendations and risk-reducing strategies for contralateral breast cancer.

Treatment Algorithm Summary

For stage IIIA HER2-positive breast cancer in young women, the evidence-based treatment algorithm is:

1. Complete staging workup including imaging to rule out metastatic disease 2
2. Core needle biopsy with ER, PR, and HER2 testing 1, 3
3. Neoadjuvant chemotherapy: AC × 4 cycles followed by taxane + trastuzumab × 4 cycles 4
4. Definitive surgery: Mastectomy with axillary dissection (or breast conservation if adequate response) 2
5. Adjuvant trastuzumab: Complete one year total (including neoadjuvant portion) 4
6. Post-mastectomy radiation: Chest wall and regional nodes for initial T3 or N+ disease 2
7. Endocrine therapy: Tamoxifen or ovarian suppression + AI for 5-10 years 2, 5
8. Long-term surveillance: Clinical exams, annual mammography, cardiac monitoring 2, 4