ADCs in Breast Cancer Treatment: Current Landscape and Future Directions

Antibody drug conjugates (ADCs) represent a key cornerstone in treatment of early or metastatic breast cancer with HER2-alterations, demonstrating critically important improvements in response, survival, and safety. With the increasing efficacy of ADCs in HER2-positive breast cancer, there is ongoing debate over optimal combinations and sequencing, and research into expanding use for other subtypes.

At the 2025 San Antonio Breast Cancer Symposium, experts discussed the evolving role of ADCs in breast cancer care, covering their use in early-stage disease and optimal sequencing in metastatic settings.

ADCs

ADCs are a type of targeted therapy capable of honing in on specific antigens on tumor cells, such as HER2 or TROP-2. ADC molecules are composed of 3 key parts: an antibody, a payload, often topoisomerase I inhibitors, or microtubule inhibitors like emtansine; and a linker to connect the antibody to the payload, which can be cleavable or non‑cleavable.¹

[Image of Visualization of an antibody drug conjugate | Image Credit: © Aryan – stock.adobe.com]

after the antibody binds to the antigen on the tumor cell surface, the ADC-antigen complex is internalized into the cell and the drug is released from the linker, leading to the payload release.¹

“Because ADCs localize the payload to tumor cells, we can broaden that therapeutic window, allowing potent agents to be used with better tolerability,” explained Sybille Loibl, MD, associate professor of obstetrics and gynecology at the Goethe University of Frankfurt. “That widening of the therapeutic index underlies many of the efficacy

## Antibody-Drug Conjugates in Breast Cancer Treatment

In treatment of heavily pretreated patients with early breast cancer, T-DXd demonstrates high responses and improved survival. According to data from the DESTINY‑Breast05,post-neoadjuvant T‑DXd showed a superior IDFS benefit over T‑DM1 (~ 50% relative improvement) in patients with high‑risk residual HER2+ breast cancer without pCR,leading to possible future shifts in standard care.¹

in HER2+ metastatic settings, T-DXd continues to outperform T-DM1. The DESTINY‑Breast03 trial (NCT03529110)⁵ showed T-DXd had superior PFS and OS compared with T-DM1 in the second line.¹

In terms of safety, T-DM1 is generally well-tolerated with well-established side effects including fatigue, thrombocytopenia, transaminase elevations, and mild neuropathy. T-dxd was associated with higher rates of certain adverse events such as nausea and vomiting, stomatitis, constipation, peripheral sensory neuropathy, risk of interstitial lung disease (ILD), and risk of radiation pneumonitis. no previously unrecognized adverse events were observed with T-DXd in the early breast cancer trials, though effective AE management and thoughtful patient selection remain essential.¹

## Trop-2 Targeting ADCs

TROP-2 targeting ADCs are agents that bind to the TROP-2 antigen, which is expressed in various solid tumors including breast cancer. As of 2025, SG and Dato-DXd are both approved for treatment of metastatic breast cancer, including HR+, HER2-negative (HER2-) populations, and triple-negative breast cancer that is refractory to standard therapies.¹

SG is a TROP-2-targeting ADC that delivers the cytotoxic payload SN-38 directly to TROP-2 expressing tumor cells to induce apoptosis. In the TROPICS-02 trial (NCT03901339),⁶ SG showed improvement in PFS and overall survival OS in heavily pretreated HR+, HER2- metastatic breast cancer compared with treatment of physicianS choice. SG led to high intracranial response rates observed in phase 0 and real-world studies, which is attributed to SG’s pH-sensitive linker and central nervous system (CNS)-penetrant SN-38 payload.¹

“The unique linker and payload of SG may facilitate better penetration and activity in brain metastases,demonstrated in preclinical and early-phase clinical data,” said Loibl.¹

median OS data were also favorable; patients with CNS metastases achieved more than 30 months of survival, with response rates reaching 50% in some cohorts. These findings highlight SG’s meaningful intracranial activity and its emerging role in a population historically associated with poor outcomes.¹

Common toxicities associated with treatment include neutropenia and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, with growth factor support often required for patients at higher risk. additional AEs may include hair loss and fatigue.¹

Dato-DXd is the most recently approved ADC for patients with unresectable or metastatic, HR+/HER2- (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy. The TROPION-Breast01 trial (NCT05104866),⁷ which supported Dato-DXd’s approval, tested Dato-DXd in patients who had previously received 1 or 2 lines of chemotherapy for metastatic disease compared to the physician’s choice of chemotherapy.¹

The trial demonstrated a median PFS of 6.9 months with Dato-DXd compared with 4.9 months in the chemotherapy arm, along with a longer time to subsequent therapy among pa

Antibody-Drug Conjugates in HER2-Positive Breast Cancer: Emerging Strategies and Future Directions

Antibody-drug conjugates (ADCs) have revolutionized the treatment landscape for HER2-positive breast cancer, offering targeted delivery of cytotoxic agents directly to tumor cells. Trastuzumab emtansine (T-DM1) was the first ADC approved for this disease,demonstrating improved progression-free survival and overall survival compared to customary chemotherapy in patients with pre-treated metastatic HER2-positive breast cancer.

However, the field has rapidly evolved beyond T-DM1. Newer generation ADCs, such as trastuzumab deruxtecan (T-DXd), have shown remarkable efficacy, even in patients who have progressed on prior HER2-targeted therapies. T-DXd utilizes a more potent cytotoxic payload and a cleavable linker, resulting in enhanced tumor penetration and bystander killing of neighboring cells.Clinical trials have demonstrated significant improvements in progression-free survival and overall survival with T-DXd compared to standard chemotherapy regimens.

Ongoing research is focused on optimizing the sequencing of ADCs and combining them with other therapies, such as pertuzumab and chemotherapy. A key area of investigation is determining the optimal time to introduce ADCs in the treatment pathway – whether upfront, after progression on dual HER2 blockade, or in the neoadjuvant setting.Studies are evaluating trastuzumab emtansine plus pertuzumab compared with chemotherapy plus trastuzumab and pertuzumab (1, 2), as well as T-DXd alone or in sequence with THP versus standard treatment (3).

The growth of novel ADCs targeting different HER2 epitopes and utilizing alternative payloads is also underway.Biomarker research is crucial for identifying patients most likely to benefit from specific ADCs and for predicting resistance mechanisms. Ultimately, the field continues to move toward a more personalized, risk-adapted approach that aims to maximize efficacy while preserving quality of life for patients.

REFERENCES

1. Waks A, loib S, Mahtani R, et. Educational Session 6: ADCs. present at: SABCS 2025. December 9-12,
2. A study evaluating trastuzumab emtansine plus pertuzumab compared with chemotherapy plus trastuzumab and pertuzumab for participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Clinicaltrials.gov. Updated July 2, 2019. Accessed December 11,2025. https://clinicaltrials.gov/study/NCT02131064
3. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. Clinicaltrials.gov. Updated November 18, 2025. Accessed December 11, 2025.

Peripheral Neuropathy: A Thorough Guide

Peripheral neuropathy is a condition that affects millions of people, causing pain, numbness, and weakness in the hands and feet. It’s not a disease itself,but rather a symptom of an underlying issue. let’s break down what it is indeed, what causes it, and how you can manage it.

What is Peripheral Neuropathy?

Your peripheral nervous system sends facts from your brain and spinal cord to the rest of your body. When these nerves are damaged,it disrupts interaction,leading to the symptoms of peripheral neuropathy. It can affect one nerve or many, and symptoms can range from mild to debilitating.

What causes Peripheral Neuropathy?

There are many potential causes. Here are some of the most common:

• Diabetes: this is the most frequent cause. High blood sugar levels can damage nerves over time.
• Injuries: Trauma from accidents, falls, or repetitive motions can injure peripheral nerves.
• Infections: Certain infections, like shingles, Lyme disease, and HIV, can cause neuropathy.
• Autoimmune Diseases: Conditions like rheumatoid arthritis, lupus, and Guillain-Barré syndrome can attack the nerves.
• vitamin Deficiencies: Lack of vitamins B12, B1, E, and others can contribute to nerve damage.
• Exposure to Toxins: Certain chemicals,heavy metals,and medications (like chemotherapy drugs) can be toxic to nerves.
• Inherited Disorders: Some types of neuropathy are genetic.
• Alcoholism: Excessive alcohol consumption can lead to nerve damage.

Symptoms of peripheral Neuropathy

Symptoms vary depending on the nerves affected.Common signs include:

• Numbness or tingling in hands and feet
• Sharp, burning, or shooting pain
• Extreme sensitivity to touch
• Loss of balance and coordination
• Muscle weakness
• Difficulty with everyday tasks like buttoning clothes or walking

How is Peripheral Neuropathy Diagnosed?

Diagnosing neuropathy involves a few steps. Your doctor will likely:

• Review your medical history: They’ll ask about your symptoms, any underlying conditions, and medications your taking.
• Perform a physical exam: This includes checking your reflexes, muscle strength, and ability to feel pain, temperature, and vibration.
• Order nerve tests: These can include:
  • nerve conduction studies: Measure how quickly electrical signals travel through your nerves.
  • Electromyography (EMG): Assesses the electrical activity of your muscles.
• Blood tests: To check for underlying conditions like diabetes or vitamin deficiencies.
• Nerve biopsy: In rare cases, a small sample of nerve tissue might potentially be taken for examination.

Managing Peripheral Neuropathy

While there’s often no cure, you can manage symptoms and slow the progression of neuropathy. Treatment focuses on addressing the underlying cause and relieving pain.Here’s what can definitely help:

• medications: Pain relievers (over-the-counter or prescription), antidepressants, and anticonvulsants can help manage nerve pain.
• Physical Therapy: Exercises can help maintain muscle strength and improve balance.
• Occupational Therapy: Can definitely help you adapt to daily tasks and use assistive devices.
• Lifestyle Changes:
  • Manage diabetes: Keep blood sugar levels under control.
  • Eat a healthy diet: Focus on nutrient-rich foods.
  • Exercise regularly: Improves circulation and nerve health.
  • Avoid alcohol and smoking: These can worsen neuropathy.
• Alternative Therapies: Some people find relief with acupuncture, massage, or transcutaneous electrical nerve stimulation (TENS).

Current Research & Clinical Trials

Researchers are continually working on new treatments for peripheral neuropathy. You can find information about ongoing clinical trials at https://clinicaltrials.gov/study/NCT03529110.

When to See a Doctor

if you experience persistent numbness, tingling, or pain in your hands or feet, it’s important to see a doctor.Early diagnosis and treatment can help prevent further nerve damage and improve your quality of life. Don’t ignore these symptoms – they could be a sign of something serious.