New inhibitor drug used for patients with the most common type of stage four breast cancer

Ms Christina Ng, 59, first felt pain in her upper left arm about six years ago. It started as a dull ache that wouldn't go away.

"I thought it was caused by stress so I decided to quit my job as an accountant. But the pain got more intense. It would creep into my fingertips," the breast cancer survivor told The Straits Times in an interview last week.

"The pain got so bad that I would cry. It was a throbbing pain that came two or three times a day and it lasted for 20 minutes each time at the beginning. Later, the pain would last for about an hour each time."

But though the pain was so bad that it would wake her up at night, Ms Ng - whose breast cancer had been in remission for about 10 years - did not think it was very serious. She had undergone a mastectomy, chemotherapy and radiation therapy in 2000.

"I thought it was gout. I complained about all the protein I was eating, and I went to see the polyclinic doctor, who gave me painkillers."

In 2013, when she went to Tan Tock Seng Hospital for a follow-up health check, she had lost weight - 7kg over six months - and was coughing.

She was referred to the National Cancer Centre Singapore (NCCS) where she found out her cancer had recurred and spread from her breast to her lungs. There was a lump growing under her left arm that was causing her the pain. Furthermore, there was no cure for patients like her with stage four breast cancer - only treatment to improve the quality of life and prolong it.

"I didn't want to accept it. Then, I told myself that my children are much older and could take care of themselves, though I did wish to live longer," said Ms Ng, as tears welled up in her eyes.

Her two sons were 11 and four when she was first diagnosed with stage three breast cancer in 2000.

According to the Singapore Cancer Registry, 910 women here were diagnosed with stage four breast cancer between 2011 and 2015, a 32 per cent increase from 697 women between 2006 and 2010.

Around the world, an estimated 250,000 women are diagnosed with advanced breast cancer each year.

At NCCS, Ms Ng was given morphine for her "excruciating pain".

"I even went to see a hospice doctor," she said.

Fortunately for her, in August 2014, the opportunity arose for her to try out a new drug when she enrolled in the phase III Monaleesa-2 study.

More than four years later, Ms Ng no longer experiences pain and a scan in November last year showed the mass in her underarm had shrunk by 90 per cent.

The phase III Monaleesa-2 study involves 668 patients from 294 clinical trial sites around the world, including nine patients from NCCS. It aims to study a new treatment option, Ribociclib, which is used in combination with a hormone therapy called letrozole.

Enrolment for the study has ended.

Results of the phase III study showed that the treatment leads to a reduction in tumour size as well as reduced risk of disease progression and death by 43 per cent.

In January this year, the Health Sciences Authority here approved Ribociclib, sold under the brand name Kisqali, as a first-line treatment option for postmenopausal women with metastatic hormone receptor-positive, HER2-negative breast cancer, the most common type of stage four breast cancer.

The entry of Kisqali has meant a sea change in the treatment of such late-stage cancer. The drug does not work for other types of breast cancer.

"In the past, some people had reservations about using anti-hormone treatment by itself, first as they had the perception it was not as effective as chemotherapy," said Dr Yap Yoon Sim, a senior consultant at NCCS and a global steering committee member of the Monaleesa-2 study, which is run by pharmaceutical company Novartis.

The study showed that anti-hormone treatment, when used with Kisqali, led to a median progression-free survival rate of 25 months, compared with 16 months without the use of Kisqali, she said. This meant the cancer patients lived longer without the cancer getting worse.

In Ms Ng's case, her pain improved quite dramatically with the use of Kisqali, noted Dr Yap.

"Chemotherapy might have worked just as quickly for Christina but the thing with chemo is that patients might have to stop the treatment after around six months, and switch to something else," she said.

This is because the therapy may have cumulative side effects and is also stressful as it necessitates a hospital visit for the patient to be given the drug by injection.

"Breast cancer patients on chemo feel more tired, their risk of infections goes up, they might have tingling and numbness in their hands and feet, depending on the type of drugs used. Some drugs may affect heart function," she said.

"With Kisqali, the most common side effect is a drop in white blood cells, but most of the time, they don't feel anything and the risk of infections is not significantly increased."

Dr Wong Seng Weng, the medical director and consultant medical oncologist at The Cancer Centre, said the availability of Kisqali - which is known as a CDK 4/6 inhibitor - has had a tremendous impact on the way he treats his patients who have advanced breast cancer.

"Whereas in the past, I would have reached for chemotherapy as first choice in cases of advanced breast cancer in a crisis situation, I have now replaced chemotherapy, where suitable, with the CDK 4/6 inhibitor in combination with anti-hormonal treatment as the default," said Dr Wong.

"These patients often have their cancer controlled for a much longer period than if I were to use anti-hormonal treatment alone. It has let me defer the use of chemotherapy much longer, hence avoiding the exposure of my advanced breast cancer patients to the side effects of chemotherapy.

"By adding this class of drugs to the long-established approach of anti-hormonal treatment in this group of patients with advanced breast cancer, the risk of death or worsening of the cancer is cut by half compared with the older treatment of using anti-hormonal treatment alone."

Dr Wong recently saw an advanced breast cancer patient whose cancer had ruptured through the affected breast, leading to persistent and profuse bleeding.

"After starting the patient on Ribociclib, her condition rapidly improved within six weeks and the tumour shrank significantly, accompanied by the arrest of the profuse bleeding," he said.

"I consider the discovery of this class of breast cancer drugs one of the most important breakthroughs in the last decade."

The major limitation of CDK 4/6 inhibitors, he said, is that they do not deliver the Holy Grail of permanently curing patients with advanced breast cancer.

Nevertheless, Ms Ng is thankful for the drug as it has helped to reduce her suffering and she can spend quality time with her family.

"I don't know what's in store for me in the future but I don't want to have the pain back and I do think I've a high pain tolerance," she said.

"Every step along the way, I am consoled because there are people around me. There's goodness around me."

She advises newly diagnosed cancer patients to talk about their illness.

"Just tell somebody. Don't keep it to yourself," said Ms Ng. "I think it helps you to let go as well because you need to be at peace internally in order to cope with your illness."

Blocking growth and spread of cancer

Ribociclib is a drug that blocks the growth and spread of cancer, by targeting and interfering with processes in the cells that cause cancer to grow.

It is the second drug of this class approved for use in Singapore, after the Health Sciences Authority approved Palbociclib, sold under the brand name Ibrance, in July 2016.

This class of drugs, called CDK 4/6 inhibitors, belongs to a family of anti-cancer drugs known as targeted therapy. They are taken orally.

There are now three CDK 4/6 inhibitors approved for use in the United States. They are suited to the treatment of advanced breast cancers that are dependent on the female hormones of the body to stimulate their growth (oestrogen receptor (ER) positive breast cancer), said Dr Wong Seng Weng, the medical director and consultant medical oncologist at The Cancer Centre.

Almost two-thirds of women with advanced breast cancer belong to this category, he said.

This class of drugs shines when compared with conventional chemotherapy, he said.

"Chemotherapy would be akin to conventional artillery with much collateral damage to innocent bystanders and Ribociclib would mirror a smart bomb with equally good mission success rate but much lower civilian casualty," he said.

"In other words, Ribociclib and Palbociclib can achieve the same treatment outcomes as chemotherapy with much lower side effects, resulting in a much improved quality of life."