Overview of Breast Cancer Treatment

Breast cancer is the most common cancer among women worldwide and the second leading cause of cancer death in women. Treatment has evolved dramatically over the past two decades with the introduction of targeted therapies, immunotherapy, and precision medicine approaches based on molecular subtyping.

Molecular Subtypes & Treatment Approaches

HR+/HER2- (Hormone Receptor Positive, HER2 Negative) - 70% of cases

  • Endocrine therapy (aromatase inhibitors, SERMs, SERDs)
  • CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib)
  • PI3K inhibitors for PIK3CA-mutated disease

HER2+ (HER2 Positive) - 20% of cases

  • HER2-targeted antibodies (trastuzumab, pertuzumab)
  • Antibody-drug conjugates (T-DM1, T-DXd)
  • Tyrosine kinase inhibitors (neratinib, tucatinib)

Triple-Negative (HR-/HER2-) - 10-15% of cases

  • Chemotherapy (anthracyclines, taxanes)
  • Immunotherapy (pembrolizumab for PD-L1+ disease)
  • PARP inhibitors for BRCA-mutated disease
  • Antibody-drug conjugates (sacituzumab govitecan)

Epidemiology & Impact

Breast cancer remains the most commonly diagnosed cancer among women worldwide, with approximately 2.3 million new cases annually. In the United States, an estimated 310,720 new cases of invasive breast cancer are expected in 2024, along with 56,500 cases of ductal carcinoma in situ (DCIS). The lifetime risk for women is approximately 1 in 8 (13%), though this varies significantly based on genetic predisposition, family history, reproductive factors, and lifestyle variables. Incidence rates have increased modestly (~0.5% per year) largely attributed to improved detection through screening mammography and rising obesity prevalence. Mortality, however, has declined by approximately 43% since 1989, reflecting advances in both early detection and systemic therapy. Racial disparities persist: Black women have a 40% higher mortality rate compared to White women despite similar incidence, driven by differences in tumor biology (higher rates of triple-negative disease), access to care, and socioeconomic factors.

Molecular Biology & Biomarkers

The molecular classification of breast cancer fundamentally guides treatment decisions. The four major intrinsic subtypes — Luminal A (HR+/HER2−, low Ki-67), Luminal B (HR+/HER2− high Ki-67 or HR+/HER2+), HER2-enriched (HR−/HER2+), and Basal-like/Triple-negative (HR−/HER2−) — have distinct biology, prognosis, and therapeutic vulnerabilities. Genomic assays such as Oncotype DX (21-gene recurrence score) and MammaPrint (70-gene signature) have transformed adjuvant treatment decisions by identifying patients with early-stage HR+ disease who can safely omit chemotherapy, sparing thousands of patients from unnecessary toxicity annually. Beyond the classic subtypes, emerging molecular targets include PIK3CA mutations (found in ~40% of HR+ tumors, targetable with alpelisib or inavolisib), ESR1 mutations (arising during endocrine therapy, targetable with elacestrant), AKT pathway alterations, and TROP-2 expression (targeted by sacituzumab govitecan). BRCA1/2 germline mutations, present in 5-10% of all breast cancers, confer sensitivity to PARP inhibitors (olaparib, talazoparib) and have reshaped both treatment and prevention strategies.

Evolving Treatment Landscape

The therapeutic landscape for breast cancer has undergone remarkable expansion. In HR+/HER2− disease, CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) combined with endocrine therapy have become the standard first-line approach for metastatic disease, approximately doubling progression-free survival. Ribociclib and abemaciclib have also gained adjuvant indications, representing a paradigm shift in early-stage management. The antibody-drug conjugate (ADC) revolution has been transformative: trastuzumab deruxtecan (Enhertu) has demonstrated unprecedented activity across HER2-positive and HER2-low tumors, effectively expanding the treatable HER2 population from ~20% to ~60% of all breast cancers. Sacituzumab govitecan (Trodelvy) has improved outcomes in both triple-negative and HR+ pretreated disease. In 2024, the first tumor-infiltrating lymphocyte (TIL) therapy, lifileucel (Amtagvi), was approved for melanoma, with breast cancer trials underway. The integration of ctDNA (circulating tumor DNA) monitoring is poised to further personalize treatment by enabling minimal residual disease detection and early relapse identification.

Approved Breast Cancer Therapies

Herceptin
trastuzumab
FDA Approved 1998 Frontline
Approved Indications (US/FDA)
Treatment of patients with HER2-overexpressing metastatic breast cancer; Adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR negative or with high risk features) breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; As a single agent following multi-modality anthracycline-based therapy.
Dosing Schedule
Weekly Regimen: Loading dose 4 mg/kg IV over 90 minutes; Maintenance 2 mg/kg IV weekly over 30 minutes
Every 3 Weeks: Loading dose 8 mg/kg IV over 90 minutes; Maintenance 6 mg/kg IV every 3 weeks over 30-90 minutes
Cycle Length
Weekly or every 3 weeks depending on regimen
Combination Therapy
With paclitaxel (175 mg/m² every 3 weeks); With docetaxel (75-100 mg/m² every 3 weeks); With doxorubicin (60 mg/m²) + cyclophosphamide (600 mg/m²); With carboplatin (AUC 6 every 3 weeks)
Manufacturer
Genentech
Approval Year
1998
Pivotal Trial
NCT00004067 ↗
Key Publication
Piccart-Gebhart et al. NEJM 2005 ↗
Perjeta
pertuzumab
FDA Approved 2012 Frontline
Approved Indications (US/FDA)
Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (greater than 2 cm or node positive); Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence; With trastuzumab and docetaxel for HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Dosing Schedule
Initial Dose: 840 mg IV over 60 minutes
Maintenance: 420 mg IV over 30-60 minutes every 3 weeks
Cycle Length
Every 3 weeks
Combination Therapy
With trastuzumab (loading 8 mg/kg, then 6 mg/kg every 3 weeks) and docetaxel (75-100 mg/m² every 3 weeks); May use fixed-dose subcutaneous combination Phesgo: loading 1200 mg pertuzumab + 600 mg trastuzumab, then 600 mg/600 mg every 3 weeks; Duration: up to 18 cycles (1 year) for neoadjuvant/adjuvant settings.
Manufacturer
Genentech
Approval Year
2012
Pivotal Trial
NCT00567190 ↗
Key Publication
Baselga et al. NEJM 2012 (BOLERO-2) ↗
Ibrance
palbociclib
FDA Approved 2015 Frontline
Approved Indications (US/FDA)
Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women; In combination with fulvestrant in women with disease progression following endocrine therapy; In men with HR-positive, HER2-negative advanced or metastatic breast cancer.
Dosing Schedule
125 mg orally once daily for 21 consecutive days followed by 7 days off treatment
Cycle Length
28-day cycle (21 days on, 7 days off)
Combination Therapy
With aromatase inhibitor (letrozole 2.5 mg daily, anastrozole 1 mg daily, or exemestane 25 mg daily); Or with fulvestrant (500 mg IM on days 1, 15, 29, then monthly); May also combine with inavolisib (9 mg daily) and fulvestrant for PIK3CA-mutated disease.
Manufacturer
Pfizer
Approval Year
2015
Pivotal Trial
NCT01740427 ↗
Key Publication
Finn et al. NEJM 2016 ↗
Kisqali
ribociclib
FDA Approved 2017 Frontline
Approved Indications (US/FDA)
HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; In combination with fulvestrant in postmenopausal women or in men with disease progression following endocrine therapy; Adjuvant treatment of HR-positive, HER2-negative early breast cancer at high risk of recurrence.
Dosing Schedule
Advanced Disease: 600 mg orally once daily for 21 days followed by 7 days off
Early Breast Cancer (Adjuvant): 400 mg orally once daily for 21 days followed by 7 days off
Cycle Length
28-day cycle (21 days on, 7 days off)
Combination Therapy
With nonsteroidal aromatase inhibitor (NSAI: letrozole 2.5 mg or anastrozole 1 mg daily); Or with fulvestrant (500 mg IM on days 1, 15, 29, then monthly); Duration: 3 years for early breast cancer (adjuvant setting based on NATALEE trial, September 2024 approval), until disease progression for advanced disease.
Manufacturer
Novartis
Approval Year
2017
Pivotal Trial
NCT01958021 ↗
Key Publication
Cortés et al. NEJM 2022 ↗
Verzenio
abemaciclib
FDA Approved 2017 Frontline
Approved Indications (US/FDA)
HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant; As monotherapy for HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy; Adjuvant treatment of HR-positive, HER2-negative early breast cancer at high risk of recurrence.
Dosing Schedule
With Endocrine Therapy: 150 mg orally twice daily continuously
As Monotherapy: 200 mg orally twice daily continuously
Cycle Length
Continuous daily dosing (no scheduled breaks, unlike palbociclib/ribociclib)
Combination Therapy
With aromatase inhibitor (letrozole, anastrozole, or exemestane); Or with fulvestrant (500 mg IM on days 1, 15, 29, then monthly); Can be used as monotherapy for heavily pretreated patients; Duration: 2 years for adjuvant early breast cancer.
Manufacturer
Eli Lilly
Approval Year
2017
Pivotal Trial
NCT02107703 ↗
Key Publication
Hortobagyi et al. NEJM 2016 ↗
Kadcyla
ado-trastuzumab emtansine (T-DM1)
FDA Approved 2013 Second-line
Approved Indications (US/FDA)
HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane; Adjuvant treatment of HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
Manufacturer
Genentech
Approval Year
2013
Pivotal Trial
NCT00829166 ↗
Key Publication
Verma et al. NEJM 2012 ↗
Enhertu
fam-trastuzumab deruxtecan-nxki (T-DXd)
FDA Approved 2019 Third-line+
Approved Indications (US/FDA)
HER2-positive unresectable or metastatic breast cancer after two or more prior anti-HER2 based regimens; HER2-low (IHC 1+ or IHC 2+/ISH-) unresectable or metastatic breast cancer after prior chemotherapy.
Manufacturer
Daiichi Sankyo/AstraZeneca
Approval Year
2019
Pivotal Trial
NCT03248492 ↗
Key Publication
Bardia et al. NEJM 2021 ↗
Trodelvy
sacituzumab govitecan-hziy
FDA Approved 2020 Relapsed/Refractory
Approved Indications (US/FDA)
Unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one for metastatic disease; HR-positive, HER2-negative unresectable locally advanced or metastatic breast cancer who have received endocrine-based therapy and at least two additional systemic therapies.
Manufacturer
Gilead Sciences
Approval Year
2020
Pivotal Trial
NCT02574455 ↗
Key Publication
Bardia et al. NEJM 2021 (ASCENT) ↗
Keytruda
pembrolizumab
FDA Approved 2020 Frontline
Approved Indications (US/FDA)
With chemotherapy for locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test; High-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment.
Dosing Schedule
200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
Combination Therapy
With chemotherapy: paclitaxel (175 mg/m² every 3 weeks) or nab-paclitaxel (100 mg/m² weekly), plus carboplatin (AUC 5-6 every 3 weeks or AUC 2 weekly); Continue until disease progression, unacceptable toxicity, or up to 24 months.
Manufacturer
Merck
Approval Year
2020
Pivotal Trial
NCT02819518 ↗
Key Publication
André et al. NEJM 2019 ↗

Treatment Sequencing & Clinical Considerations

First-Line Therapy Selection

Treatment selection depends on molecular subtype, stage, menopausal status, and patient preferences. For HR+/HER2- disease, CDK4/6 inhibitors combined with endocrine therapy have become standard first-line treatment for most patients based on significant progression-free survival benefits demonstrated in PALOMA-2, MONALEESA-2, and MONARCH-3 trials.

For HER2+ disease, dual HER2 blockade with trastuzumab and pertuzumab combined with chemotherapy is standard first-line therapy, supported by the CLEOPATRA trial showing overall survival benefit. In the adjuvant setting, duration of HER2-targeted therapy ranges from 6 months to 1 year depending on clinical and pathologic risk factors.

CDK4/6 Inhibitor Differences

While all three CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) demonstrate efficacy, key differences exist:

  • Palbociclib: Intermittent dosing (3 weeks on, 1 week off), neutropenia most common adverse event
  • Ribociclib: Intermittent dosing, QTc prolongation monitoring required, approved for adjuvant use (3-year duration based on NATALEE trial)
  • Abemaciclib: Continuous dosing, diarrhea most common adverse event, approved as monotherapy and for adjuvant use (2-year duration)

Emerging Therapies & Future Directions

The breast cancer treatment landscape continues to evolve with novel antibody-drug conjugates, oral SERDs, PI3K/AKT/mTOR pathway inhibitors, and PARP inhibitors for BRCA-mutated disease. Datopotamab deruxtecan and other Trop-2 targeting agents show promise for triple-negative disease. Capivasertib in combination with fulvestrant demonstrates benefit in AKT pathway-altered tumors.