Improving Outcomes in Metastatic Breast Cancer Through Novel Therapies and Personalized Care

Sara Giordano MD, Senior Physician at Dana Farber Cancer Institute, Breast Medical Oncology; Pooja Patel MD, Senior Fellow of Hematology and Oncology at Dana Farber Cancer Institute at Brighton, MA.

In this interview, Sara Giordano, MD, and Pooja Patel, MD, discuss recent advancements in targeted therapies for metastatic breast cancer, the growing role of personalized medicine, and emerging treatments that aim to improve patient outcomes.

Please introduce yourself by stating your name, title, and any relevant clinical experience you’d like to share.

Sara Giordano MD, Senior Physician at Dana Farber Cancer Institute, Breast Medical Oncology. Written in conjunction with Pooja Patel MD, Senior Fellow of Hematology and Oncology at Dana Farber Cancer Institute at Brighton, MA.

Could you discuss the latest developments in targeted therapies for metastatic breast cancer and how they are influencing treatment protocols?

In the treatment landscape of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer, two significant developments have emerged with US Food and Drug Administration approval in the past few months. Most recently, datopotamab deruxtecan (Dato-DXd) was approved on January 17, 2025, based on TROPION-Breast01 Study. In this phase 3 trial, Dato-DXd demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard chemotherapy in patients with metastatic HR+, HER2-low, or HER2-negative breast cancer. The median PFS was 6.9 months for patients treated with Dato-DXd, vs 4.9 months for those receiving chemotherapy, reflecting a 37% reduction in the risk of disease progression or death. Based on these results, Dato-DXd is now being considered a viable option to use as second-line therapy after the progression of the disease on CDK4/6 inhibitors and an aromatase inhibitor.

We also have inavolisib combined with palbociclib and endocrine therapy in HR+, HER2-negative, endocrine-resistant, PIK3CA-mutated breast cancer which received FDA approval October 10, 2024, based on the INAVO 120 trial. In this phase 3 trial, the triplet (inavolisib + palbociclib + endocrine therapy) was compared to placebo + palbociclib + endocrine therapy. The median PFS was 15 months in the inavolisib arm vs 7.3 months in the standard-of-care arm. This is the first time a selective PIK3CA inhibitor has demonstrated both safety and efficacy in combination with a CDK4/6 inhibitor. This could be a new first-line option for endocrine-resistant, PIK3CA-mutated advanced breast cancer.

What has your research revealed about the efficacy and safety of combining CDK4/6 inhibitors with endocrine therapy in treating HR-positive, HER2-negative metastatic breast cancer?

CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) remains standard first-line treatment in HR+, HER2-negative metastatic breast cancer due to their ability to delay disease progression and improve survival. Across all major trials, these agents have nearly doubled the time to disease progression. Abemaciclib (MONARCH-3) showed the longest PFS extension (~28.2 months vs. 14.8 months, ~1.9x increase), while ribociclib (MONALEESA-2 & MONALEESA-7) demonstrated the most consistent overall survival benefit. Triple-negative breast cancer has also seen progress with immunotherapy (pembrolizumab for PD-L1-positive tumors), PARP inhibitors (for BRCA mutations), and antibody-drug conjugates (ADCs), such as sacituzumab govitecan.

How is the concept of personalized medicine being applied in metastatic breast cancer care, and what challenges remain in its implementation?

Personalized medicine plays a crucial role in optimizing treatment plans for patients with metastatic breast cancer. Molecular profiling and genetic testing help tailor therapies to an individual's tumor characteristics, ensuring more effective and targeted treatments. Accessibility to next-generation sequencing (NGS), widely available in large cancer centers, should be universally accessible to all breast cancer patients to identify actionable mutations.

For HR+, HER2-negative metastatic breast cancer, CDK4/6 inhibitors remain the standard first-line therapy. However, for patients who develop resistance, PI3K inhibitors such as alpelisib or inavolisib, and selective estrogen receptor degraders (SERDs) such as elacestrant are essential for treating tumors with PI3KCA or ESR1 mutations. Additionally, understanding BRCA1 and BRCA2 mutation status is pivotal, as PARP inhibitors (olaparib and talazoparib) are approved for BRCA-mutated, HER2-negative metastatic breast cancer, offering a more targeted approach.

All this to say, it is certainly challenging to implement personalized medicine effectively. Limited access to comprehensive genomic profiling, the high cost of targeted therapies, and tumor heterogeneity leading to resistance are ongoing hurdles. The time it takes to obtain the results for NGS can also pose a challenge. Expanding access to molecular testing and, in turn, focusing on targetable therapies will be key in further improving outcomes for patients with metastatic breast cancer.

Are there any patient-reported outcomes or quality-of-life metrics that you feel are underutilized in assessing treatment effectiveness in metastatic breast cancer?

Due to time constraints and the complexity of the disease, many patients are not formally assessed using standardized quality-of-life measurement tools. Instead, we often rely on patients to verbally report symptoms and concerns related to ongoing therapy, which is not the best thing at times as it may not fully capture the impact on their overall well-being. But we try our best.

In our clinic, during their initial intake with vital signs, each patient is asked to rate their pain on a scale of 1 to 10, which helps guide our discussion for during appointments. There is the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire, a validated, multidimensional questionnaire with 37 items that is mainly used in clinical trial settings. The QLQ-BR23 is a quality-of-life assessment tool specific to metastatic breast cancer. We are not using these tools with every metastatic breast cancer patient. They certainly are underutilized. At the same time, although they provide valuable insight, they may not always fully capture the broader impact on their overall well-being.

What emerging therapies or research areas do you believe hold the most promise for improving outcomes in patients with metastatic breast cancer?

There have been numerous exciting advancements in the treatment of metastatic breast cancer, with novel therapies expanding options across different subtypes. One of the most notable recent approvals is Dato-DXd, as mentioned above. Additionally, the TROPION-Breast02 (NCT05629585) phase 3 trial is evaluating Dato-DXd vs chemotherapy in first-line patients with locally recurrent, inoperable, or metastatic triple-negative breast cancer who are not candidates for PD-1/PD-L1 inhibitor therapy.

In the realm of SERDS, giredestrant, an oral SERD, is being actively studied in multiple trials for ER-positive, HER2-negative metastatic breast cancer with ESR1 mutation. The acelERA (NCT04576455) phase 2 trial is assessing giredestrant in combination with endocrine therapy as a potential treatment option. The pionERA (NCT06065748) phase 3 trial is investigating giredestrant in combination with fulvestrant and a CDK4/6 inhibitor as a first-line treatment for patients with resistance to adjuvant endocrine therapy alone.

Targeted therapy shows great promise in further improving the treatment landscape for metastatic breast cancer. These emerging therapies offer more personalized and potentially more tolerable options for those living with metastatic breast cancer.