A Safer, More Effective Treatment Option for Young Women with Stage 4 Breast Cancer

In stage 4 hormone-positive, HER2-negative breast cancer with internal-organ metastases, treatment tends to begin with chemotherapy for a faster response because the disease is expected to behave more aggressively. A new clinical trial may change this approach.

A phase 2 trial involving younger women who had not yet reached menopause, RIGHT Choice, found that the newer CDK4/6 cancer drug ribociclib (Valamor) combined with hormone therapy was much better at halting aggressive metastatic tumor growth than standard combination chemotherapy.

Women receiving ribociclib plus hormone therapy lived twice as long without worsening cancer: median progression-free survival was 24 months versus 12 months. They also had far fewer side effects.

The study was presented on 6 December 2022 at the San Antonio Breast Cancer Symposium.

Visceral Crisis Requires a Rapid Response

Visceral crisis in cancer means a high tumor burden and aggressive cancer affecting internal organs. If the liver is affected, for example, it cannot clear toxins; lung involvement may prevent adequate oxygen intake.

Rapidly acting drugs are needed to slow cancer in visceral crisis, and chemotherapy is the first option that comes to mind. This study tested the CDK4/6 inhibitor ribociclib plus hormone-blocking treatment instead of the usual first-line chemotherapy for aggressive, high-burden, hormone-positive, HER2-negative breast cancer.

The most common breast cancer type, called estrogen receptor (HR)-positive, HER2-negative, is generally diagnosed early and responds well to treatment. More than 90% of women receiving standard treatment remain alive without recurrence after 5 years.

However, a small proportion of patients have breast cancer that rapidly spreads to bones, liver, lungs and other organs, causing symptoms or impairing organ function.

For people experiencing or at risk of visceral crisis, standard treatment has been a two-drug chemotherapy combination. It often shrinks tumors quickly but can have serious side effects, encouraging research into less toxic alternatives.

Ribociclib has become widely used for HR-positive, HER2-negative breast cancer requiring treatment beyond surgery and radiation, meaning stage 4 disease. It is a targeted CDK4/6 inhibitor that switches off processes cancer cells need for division.

Combining ribociclib with a hormone-blocking medicine (endocrine therapy) has recently become standard for postmenopausal women with hormone receptor-positive, HER2-negative metastatic cancer that is not immediately life-threatening. However, younger, premenopausal women account for a substantial share of annual breast cancer diagnoses.

The proportion diagnosed in women younger than 50 ranges from around 20% in the United States to nearly half or more in parts of the Middle East and Asia. In Turkey, it is around 30%.

Rapid Tumor Response with Fewer Side Effects

The study randomized 222 premenopausal and perimenopausal women to combination chemotherapy or ribociclib plus hormone therapy.

Around half had visceral crisis when enrolled. The others had metastatic tumors causing substantial symptoms, although not yet at the level of a crisis or rapidly progressing disease.

Hormone therapy consisted of goserelin (Zoladex) to block ovarian hormone production, plus either letrozole (Femara) or anastrozole (Arimidex), both aromatase inhibitors.

Chemotherapy was one of three doublets, depending on usual local practice: docetaxel plus capecitabine (Xeloda), paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

Women in both groups could continue treatment while tumor growth remained controlled and side effects tolerable.

Disease control lasted 2 years with the ribociclib combination, compared with just over 1 year with chemotherapy.

Time to response, meaning the time until metastatic tumors began shrinking, was similar between groups.

Chemotherapy carried a higher risk of serious nausea, vomiting and diarrhea than the ribociclib combination. However, decreased white blood cell counts were more common with ribociclib.

Almost 25% receiving chemotherapy stopped at least one drug because of side effects, compared with only 7% receiving the ribociclib combination.

Moving Increasingly Away from Chemotherapy in Advanced Breast Cancer

Besides better disease control and fewer side effects, the combination reduces frequent hospital visits for chemotherapy because both ribociclib and hormone therapy are pills patients can take at home. This is important for quality of life.

However, full results still need review and publication before the combination becomes standard. Choosing subsequent treatment after progression on ribociclib is another important question.

The marked difference between groups suggests these findings deserve attention despite coming from a phase 2 study. They indicate that starting with a CDK4/6 inhibitor plus hormone suppression is the most appropriate option for young women with aggressive, advanced, hormone-positive, HER2-negative breast cancer.