What is the recommended sequence of treatment for bilateral breast discordance with Luminal A breast cancer in one breast and Luminal B (hormone receptor-positive, human epidermal growth factor receptor 2 (HER2) negative) breast cancer in the other?

Treatment Sequence for Bilateral Breast Cancer with Discordant Luminal A and Luminal B Subtypes

The treatment sequence should be dictated by the more aggressive Luminal B breast cancer, meaning chemotherapy followed by endocrine therapy should be administered to treat both breasts simultaneously, as the systemic therapy will address both tumors while the Luminal A tumor receives appropriate but not excessive treatment. 1

Treatment Rationale and Sequencing

Systemic Chemotherapy Decision

Luminal B HER2-negative breast cancer requires chemotherapy followed by endocrine therapy in the majority of cases, particularly when high clinical risk features are present (such as node-positive disease or locally advanced presentation). 1 The presence of Luminal B disease on one side establishes the indication for chemotherapy, which will treat both breasts systemically. 1

• Most Luminal A tumors do not require chemotherapy except those with highest risk of relapse (extensive nodal involvement). 1, 2 However, when bilateral disease includes a Luminal B tumor, the treatment plan must address the more aggressive biology. 1

• The decision for chemotherapy in Luminal B HER2-negative disease depends on individual recurrence risk, presumed endocrine therapy responsiveness, and patient preferences. 1

Genomic Testing Considerations

If uncertainty exists about chemotherapy necessity after considering clinical and pathological factors, gene expression assays (Oncotype DX, MammaPrint, Prosigna, Endopredict, or Breast Cancer Index) can guide the decision. 1, 2 These assays determine individual recurrence risk and predict chemotherapy benefit. 1

• Testing should ideally be performed on the Luminal B tumor, as this will determine whether chemotherapy can be safely omitted. 1, 2
• If the Luminal B tumor shows low genomic risk despite clinical classification, endocrine therapy alone may be considered. 1, 2

Recommended Treatment Algorithm

Step 1: Locoregional Treatment

• Complete surgical management of both breasts with appropriate axillary staging. 1
• Radiation therapy should be administered according to standard indications for each breast based on surgical approach and nodal involvement. 1

Step 2: Systemic Chemotherapy (if indicated)

• Chemotherapy should start within 3-6 weeks after surgery and must precede endocrine therapy. 1 Chemotherapy and endocrine therapy should not be used concomitantly (except GnRH analogues for ovarian protection). 1

• Sequential anthracycline and taxane-based regimens are standard, typically 4-8 cycles over 12-24 weeks. 1 Sequential administration is superior to concomitant use. 1

• Dose-dense schedules with G-CSF support should be considered, particularly given the proliferative nature of Luminal B tumors. 1

Step 3: Endocrine Therapy

All luminal cancers (both Luminal A and Luminal B) require endocrine therapy. 1, 2

For Premenopausal Patients:

• Tamoxifen alone for lower-risk presentations (Luminal A, stage I). 1
• For high recurrence risk (which bilateral disease with Luminal B represents), ovarian suppression combined with either tamoxifen or an aromatase inhibitor is recommended. 1

For Postmenopausal Patients:

• Aromatase inhibitors or tamoxifen followed by an aromatase inhibitor are standard options. 1
• Tamoxifen alone can be used for lower-risk tumors or if aromatase inhibitors are not tolerated. 1

Step 4: Extended Adjuvant Therapy Considerations

For high-risk early breast cancer (which bilateral disease represents), extended endocrine therapy beyond 5 years should be considered, with 7-8 years appearing sufficient for most high-risk patients. 1

Abemaciclib for 2 years in addition to endocrine therapy should be considered for stage III or high-risk stage II disease (ESMO-MCBS score: A). 1 This applies after completion of locoregional therapy and chemotherapy. 1

Bisphosphonates for up to 5 years are recommended in women without ovarian function (postmenopausal or undergoing ovarian suppression), especially if at high risk of relapse. 1

Critical Pitfalls to Avoid

Do not treat each breast as a separate entity requiring different systemic therapy sequences. Systemic therapy treats the entire patient, and attempting to sequence treatments differently for each breast is neither feasible nor evidence-based. 3, 4

Do not delay chemotherapy to start endocrine therapy first. When both are indicated, chemotherapy must precede endocrine therapy. 1 Starting systemic therapy more than 12 weeks after surgery significantly decreases efficacy. 1

Do not omit chemotherapy for the Luminal B tumor based solely on the presence of a favorable Luminal A tumor on the contralateral side. The treatment decision is driven by the more aggressive biology. 1

Ensure adequate bone health monitoring for patients on aromatase inhibitors or ovarian suppression, with calcium and vitamin D3 supplementation and periodic bone mineral density assessment. 1, 2

Avoid strong and moderate CYP2D6 inhibitors in patients on tamoxifen, or consider switching to aromatase inhibitors with ovarian suppression in premenopausal patients. 1

Timing Considerations

Radiation therapy may be delivered safely during endocrine therapy and non-anthracycline, non-taxane-based chemotherapy. 1 However, if chemotherapy and radiation are both required, chemotherapy should usually precede radiation therapy. 1

Adjuvant systemic treatment should preferably start within 3-6 weeks after surgery, with neoadjuvant therapy starting within 2-4 weeks of diagnosis completion. 1