Metastatic Breast Cancer Treatment Is Undergoing a Revolution, as Esther Shamir’s Death Highlights the Disease’s Toll

The death of singer Esther Shamir at age 71 from metastatic breast cancer has once again reminded us how present this disease is, and how deadly. According to the NCI, the U.S. National Cancer Institute, about 20% to 30% of women diagnosed at an early stage will eventually develop metastatic disease, sometimes years after they were considered cured. The metastatic form, which has spread to other organs in the body, is often diagnosed too late.

Metastatic breast cancer is defined as cancer that has spread from the breast and local lymph nodes to distant organs in the body. This does not happen overnight, cancer cells can remain hidden in the body for many years before they begin multiplying in a new site. The most common sites are the bones, lungs, liver and brain, and each has different characteristics. Bone metastases usually cause pain and increase the risk of fractures. Lung metastases cause shortness of breath. Liver metastases sometimes manifest as fatigue and loss of appetite. Brain metastases, relatively rare but the most severe, can cause headaches, vision problems and changes in memory and concentration.

"Despite the great success in early detection, it is important to understand that even after successful treatment of early breast cancer, in some women the disease may return," says Dr. Larissa Ribo, director of the oncology institute at Assuta Ashdod Hospital. "That is why women diagnosed at an early stage now receive additional treatments aimed at reducing the risk of recurrence."

The hard truth, and the reasons for hope

Metastatic breast cancer is not a single uniform entity. Tumors are classified according to three biological markers tested in biopsy, estrogen receptors, progesterone receptors, two hormones that some tumors 'use' for growth, and a protein called HER2, which speeds up cancer cell division. More than 70% of breast cancers are hormone receptor positive. About 20% to 25% are HER2 positive. And about 15% are what is known as triple negative, negative for all three markers, and this is the most aggressive type and the hardest to treat, because it has no biological 'handle' for targeted drugs to grab onto.

This classification is not just academic, it determines which drugs may work, which will not, and what the expected prognosis is. According to the NCI, the five-year survival rate in metastatic breast cancer is only 31%, compared with 99% in localized breast cancer that has not yet spread. The figures vary greatly depending on the subtype and the site of metastasis: patients with bone-only metastases usually live longer than patients with metastases to the liver, lungs or brain. But these numbers are not fixed. According to the same source, women diagnosed with metastatic breast cancer in the late 1990s had a 30% higher survival rate than women diagnosed in the early part of that decade, and treatments have advanced much further since then.

"When the disease returns in metastatic form, it is a disease that is not currently fully curable," says Dr. Ribo. "This is a difficult and upsetting moment for patients and their families. However, it is important to know that treatment for metastatic breast cancer has undergone a real revolution in the past decade. In many cases, treatments succeed in significantly extending life while preserving a good quality of life."

More and more doctors now speak of metastatic breast cancer not necessarily as a terminal disease, but as a chronic disease that can be lived with for years.

The key is early diagnosis

There is a profound gap between survival chances with breast cancer diagnosed at an early stage and the metastatic stage. A study presented a year ago at the RSNA American radiology conference found that the 10-year survival rate was 82.7% among women whose cancer was detected by mammography, compared with only 66.1% among women diagnosed by other means. The conclusion is simple, routine mammography saves lives.

"The most important message is that early detection saves lives. That is not a slogan," says Dr. Ribo. "In Israel, most breast cancer cases are diagnosed at an early stage, and the earlier the disease is detected, the higher the chances of recovery. That is why it is so important to follow the recommended screening tests, especially mammography."

Women who are not in a high-risk group are advised to undergo mammography according to the usual age-based guidelines. Women at high risk, carriers of BRCA mutations, women with a significant family history of breast or ovarian cancer, or women who previously received radiation to the chest wall, need closer follow-up and sometimes begin it at a younger age, including with MRI scans.

Dr. Ribo adds that genetic testing is now recommended in certain populations, tests that are included in the health basket: "Jewish women of Ashkenazi origin and women of Ethiopian origin have a higher prevalence of BRCA mutations. These tests, funded through the health basket, make it possible to identify women at increased risk and offer them personalized monitoring and prevention programs."

Liquid biopsy, a blood test that detects fragments of DNA from cancer cells in the bloodstream, may identify minimal residual disease one to two years before metastases can be detected on standard clinical imaging, according to studies published in Nature. The test has not yet become a full clinical standard, but studies from recent years indicate that it is moving in that direction.

Three directions that are changing the picture

Until about a decade ago, treatment for metastatic breast cancer relied mainly on classic chemotherapy that attacks rapidly dividing cells, cancerous and healthy alike. Today the picture is completely different. "If in the past we mainly had chemotherapy treatments, today many patients receive biological treatments, targeted therapies, advanced hormonal treatments and sometimes immunotherapy," says Dr. Ribo.

Three main directions are driving the change. The first is CDK4/6 inhibitors, a group of drugs that disrupt a central mechanism cancer cells use to divide. When the mechanism is blocked, the tumor stops. These drugs have become standard first-line treatment for hormone receptor positive metastatic breast cancer, about 70% of all metastatic breast cancer cases, and offer significant improvements in survival. The PATINA trial, published in the New England Journal of Medicine half a year ago, expanded their use to double positive breast cancer, positive for both hormone receptors and HER2, and found that adding palbociclib, known commercially as Ibrance, to standard treatment led to an improvement of more than 15 months in progression-free survival, 44.3 months versus 29.1 months in the control group.

The second direction is antibody-drug conjugates, a technology that links an antibody that identifies cancer cells to a chemotherapy drug, allowing precise delivery of the toxin directly to the tumor while sparing healthy tissue. Enhertu, or by its generic name trastuzumab deruxtecan, originally approved for HER2-positive cancer, was expanded two years ago for use also in patients with low levels of HER2, after a study showed better results compared with chemotherapy. Another drug from the same family, Datopotamab deruxtecan, received FDA approval last year for the treatment of hormone receptor positive breast cancer, further expanding the therapeutic tools available to doctors.

The third direction is immunotherapy, drugs that remove the "brake" cancer cells apply to the immune system, allowing the body to attack them itself. According to the American Breast Cancer organization Susan G. Komen, the KEYNOTE-355 trial, published in the New England Journal of Medicine, shows that Keytruda, by its generic name pembrolizumab, combined with chemotherapy is an effective first-line treatment for patients with triple negative cancer who are PD-L1 positive, a biological marker indicating a greater likelihood that the tumor will respond to immunotherapy. Among patients with very high PD-L1 expression, the trial showed a 27% reduction in the risk of death.

Room for hope

The 2026 health basket signaled important news for breast cancer patients in Israel. Among the treatments included this year is Enhertu for women with HER2-low metastatic breast cancer, which has demonstrated significant efficacy and reduced mortality compared with chemotherapy. In addition, the indication for Trokaph, capivasertib, was expanded, a treatment for advanced or recurrent hormone-positive, HER2-negative breast cancer, intended for patients who have exhausted previous lines of treatment.

Last month the FDA approved a new drug called Veppanu, or by its generic name vepdegestrant, the first of its kind worldwide using a technology called PROTAC, which physically breaks down the estrogen receptor in cancer cells instead of only blocking it. The drug was approved for patients with estrogen-positive, HER2-negative metastatic breast cancer who carry a specific mutation called ESR1, whose disease progressed after hormonal treatment and a CDK4/6 inhibitor. In the VERITAC-2 clinical trial, the drug reduced the risk of disease progression by 43% compared with standard hormonal treatment, with a median progression-free survival of five months versus 2.1 months in the control group.

At the same time, Datopotamab deruxtecan continues through the regulatory process, the FDA granted it Priority Review, a fast-track designation that signals potential for significant improvement over existing treatments, for first-line use in triple negative cancer not suitable for immunotherapy, and a decision is expected in the coming months.

A new molecular target called B7-H4, a protein overexpressed on the surface of cancer cells in some breast tumors, has become the target of a new drug in development called Emiltatug ledadotin. The drug has been put on the FDA fast track for approval. It offers particular hope for triple negative patients who have exhausted existing treatment options.

"The modern treatment approach does not focus only on extending life, but also on quality of life," Dr. Ribo concludes. "Our goal is for the patient to continue living her life, working, creating, raising children and grandchildren, and engaging in things that give her meaning. Alongside recognition of the difficulties that the disease brings, there is also room for real hope based on the scientific and therapeutic progress we have seen in recent years."