Triple-negative breast cancer: An overview for primary care

Last September, while the breast surgeon was telling me my breast biopsy had come back as triple-negative breast cancer (TNBC), I was initially stunned as this was not supposed to happen to me, and then I was frustrated by my ignorance. All I could remember about TNBC could fit onto the back of a postage stamp, but I knew it was the breast cancer I would least like to pick. This guide is written to help my colleagues understand the essentials of TNBC and the barriers to accessing treatment.

Don’t worry, you may not have been asleep at medical school – this terminology was only introduced in 2005 and is poorly understood. Triple negative refers to a breast cancer that does not express oestrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2). It is these receptors that are used as the targets for treatment of other breast cancer types. Without these markers, TNBC is difficult to treat.

TNBC can be described as ER-negative, PR-negative, HER2 score 0. It is a pathological description after biopsy.

TNBC is the worst type of breast cancer in terms of its aggression, recurrence and survival rates. It tends to metastasise early – within the first two years – and distantly to the brain, liver and lungs. It then becomes virtually impossible to cure with existing regimens, although there is much exciting research happening.

It tends to affect young women under age 45 and can be linked to BRCA mutations. It grows fast and can become large or metastasise within the mammogram screening interval, although it often affects those too young to be screened.

10 per cent of all breast cancers in New Zealand are TNBC

Worldwide, TNBC is thought to cause between 10 and 15 per cent of breast cancers, and it is more common in Afro-Caribbean women. In Te Rēhita Mate Ūtaetae – Breast Cancer Foundation National Register 2003–2020, 9.7 per cent of all breast cancers were TNBC, but 14.4 per cent of breast cancers in the ≤44 age group. TNBC accounts for 6.5 per cent of breast cancers in Pacific, 7.5 per cent in Māori, 10 per cent in Asian and 10.3 per cent in European women.¹

The table shows breast cancer-specific survival by receptor status of invasive tumours.¹ Looking back at survival rates for TNBC from 2003 to 2005, the five-year survival was 76 per cent, so there has been an improvement, probably linked to early detection. Moving forward, there is likely to be an improvement for those women who can afford to fund immunotherapy (from the later end of 2021).

As with most cancers, the definitive treatment is surgical, but in TNBC, gold-standard treatment also includes chemotherapy, immunotherapy and radiotherapy. Genetic testing is recommended if the patient is under age 50 as 20 per cent may have a defect in the BRCA1 or BRCA2 genes, which will have implications for the choice of surgery.

Chemotherapy – this is typically carboplatin plus paclitaxel three weekly for three months, then cyclophosphamide and doxorubicin three weekly for three months. The paclitaxel can be given in a “dose-dense” manner, which is weekly. The chemotherapy is given prior to surgery – this is called neoadjuvant chemotherapy.

Patients having chemotherapy are well served by a portacath. Hair loss is inevitable and weight gain is normal. Immunosuppression caused by the chemotherapy, and made worse by dexamethasone support, make living in a COVID world very difficult for patients to navigate.

You will see lots of red abnormal results in your inbox. As long as neutrophils are above 1x10⁹/L, haemoglobin is above 90g/L and platelets are over 100x10⁹/L, chemotherapy can generally be continued. Patients monitor their temperature and must head straight to hospital if they become febrile as febrile neutropaenia can be fatal.

Neoadjuvant chemotherapy is no more successful than adjuvant chemotherapy (ie, that given after surgery). You may be familiar with neoadjuvant chemotherapy being used to shrink large tumours to make surgical resection easier. In TNBC, the chemotherapy is given prior to surgery purely so the tumour can be examined to see if it has responded to chemotherapy.

Unlike other breast cancers, there is no hormonal drug that can be used for years after surgery to prevent recurrence, so it has to be eliminated initially. The aim of the chemotherapy is to get a complete pathological response (CPR), which is only possible to determine by histological examination of the tumour post-operatively.

If CPR is achieved, there may be no need for further treatment with chemotherapy or radiation. If CPR is not achieved, a year of additional chemotherapy may be needed (oral adjuvant capecitabine). CPR is taken as a surrogate marker for a higher chance of cure and the reduced likelihood of micrometastases being present.

Immunotherapy – the new gold-standard treatment for TNBC is chemotherapy, as above, plus one year of pembrolizumab (Keytruda), which is given intravenously every three weeks. Pembrolizumab is an anti-programmed death 1 monoclonal antibody previously shown to have antitumour activity in patients with metastatic TNBC, and more recently studied for early TNBC.

The KEYNOTE-522 trial looked at using immunotherapy (pembrolizumab) in addition to preoperative chemotherapy – 65 per cent of women in the pembrolizumab plus chemotherapy group, compared with 51 per cent in the placebo plus chemotherapy group, achieved a CPR to treatment.²

Follow-up results showed pembrolizumab plus chemotherapy reduced the risk of death by 27 per cent and the risk of disease progression or death by 34 per cent compared with chemotherapy alone.³

Surgery – removal of the tumour can normally be achieved by a lumpectomy (ie, breast-conserving surgery or BCS). However, those with a BRCA1 mutation need bilateral mastectomy and bilateral salpingo-oophorectomy.

Radiation – this is recommended after BCS to prevent local recurrence. Following mastectomy, it is only recommended if the lymph nodes are positive or the breast tumour is at least 50mm in size.

The international literature suggests that 5 per cent of patients with TNBC present with de novo metastatic disease. Unfortunately, the majority of stage IV patients relapse following treatment with curative intent.

The biological features of TNBC result in a unique clinical phenotype characterised by a propensity for visceral and brain metastases, absence of bone metastases, and typically early relapse (less than three years).

Chemotherapy remains the cornerstone of treatment as TNBC is chemosensitive but prone to relapse and resistance (the triple-negative paradox). Immunotherapy and novel treatments are showing promise.

Cancer patients are missing out on screening and effective treatments, and inequity is growing. It was disappointing that the Budget failed to give a financial boost to cancer screening to make up for the delays caused by COVID-19. The legacy of COVID-19 is that many cancers are going to be diagnosed later than they should have been. Of course, this will disproportionally affect the already vulnerable Māori and Pacific populations.

Pembrolizumab is not funded in New Zealand for TNBC, and it is unlikely that it will be for many years, if at all. The waiting list to fund prioritised modern medicines (which are Medsafe approved and recommended for funding by Pharmac’s own clinical advisory panel) is growing. The average time an approved medicine remains on the waitlist in New Zealand is 4.7 years.

The cost to a patient to fund pembrolizumab privately is approximately $8000 every three weeks, although once a cap of $60,000+GST is reached, Merck Sharp & Dohme pick up the tab. Yes, patients have to pay $9000 of GST to the government for the privilege of having a treatment course!

Few private health insurance policies pay for drugs not approved by Medsafe or funded by Pharmac.

If patients are prescribed unfunded drugs in the public system, they are often told they must fund the administration costs, although according to the Breast Cancer Foundation NZ, this is not the case at all, and administration can be paid for by DHBs.

My conscience finds it hard to live with the fact that I was able to self-fund the life-saving treatment I needed but others cannot. It is completely inequitable that only the wealthy or those able to organise fundraising (Givealittle has become the main funding pathway for those who cannot afford the very high cost) can get access to the medication they require. This is a gap that needs closing, and closing quickly, before lives are lost unnecessarily.

Given that TNBC is the most aggressive breast cancer, the most likely to metastasise, and frequently affects young women, it is a sad reflection of our health system that a new treatment effective at improving survival is not urgently fast-tracked by Te Aho o Te Kahu, the Cancer Control Agency.

Because of the way funding is siloed, no consideration is given to the far greater cost to the health system of not treating early TNBC – women whose cancer metastasises may need many courses of additional chemotherapy and radiotherapy, multiple imaging procedures, extra surgeries, inpatient stays and palliative care.

There are also other costs – the cost of them no longer working and paying tax, and the social cost of loss of a young woman who may be a mother and carer to children. I am convinced cost analyses would demonstrate how short-sighted the Ministry of Health is when it comes to giving funding to Pharmac for modern medicines.

Between 2011 and 2018, the number of publicly reimbursed modern cancer medicines in New Zealand was 7 out of a total of 90 possibilities. Compare this to 35 in Australia and 60 in the UK. Do not believe for a moment it is because these drugs are outrageously expensive to fund. As stated, spending on them will save money for the health system downstream. Further, Pharmac typically gets drugs at half the cost that individuals pay.

The cost of pembrolizumab for one year is on par with the cost of one year of renal dialysis, one coronary artery bypass graft or two knee replacements. These are all things we expect to be funded, so why not modern cancer drugs?

TNBC is just one of many conditions that has a beneficial treatment option available, but which is unfunded in New Zealand. Others include cystic fibrosis (elexacaftor/tezacaftor/ivacaftor; Trikafta), anaphylaxis (EpiPen) and lung cancer (pembrolizumab). There are many NGOs campaigning for drug funding; unfortunately, they are all competing for the same limited Pharmac budget.

I encourage you to go to the website of The Medicine Gap (themedicinegap.co.nz), run by journalist Rachel Smalley, to understand the extent of the problem we have with the lack of modern drugs in New Zealand. The Medicine Gap has no big pharma sponsorship.

While the recent Budget allocated $191 million to Pharmac over two years, it is only half of what is required. The Medicine Gap estimates $400 million is needed to pay for the modern medicines New Zealanders should expect. This is a drop in the ocean compared with the $11.1 billion given to the health reforms in this Budget.

Pharmac was given a scathing Intermin Report in December 2021. In summary, it was criticised for:⁴

• underperforming with regard to removing inequitable health outcomes
• having an excessive focus on containing costs
• using a cost-saving model that may not be the right one to meet future health needs
• its opaque decision-making, which is perceived as being slow and convoluted
• its procurement processes, which put off pharmaceutical companies from applying.

Te Aho o Te Kahu put out a report in April – Understanding the Gap: an analysis of the availability of cancer medicines in Aotearoa.⁵ It was nicely summed up as being a whitewash by Ah-Leen Rayner, chief executive of Breast Cancer Foundation NZ, who said, “Te Aho o Te Kahu’s analysis identifies just one single breast cancer drug available to Australians that Kiwis can’t access. We know of at least one other that’s been approved across the Tasman recently, and, in total, 15 unfunded breast cancer drugs meet the high benefit threshold used in Te Aho o Te Kahu’s report.

“They’re available in other countries and are recommended in international treatment guidelines. When we’re hearing from oncologists urgently wanting to prescribe drugs they believe will work for their patients who have no other options, this report is nothing but a missed opportunity to fully ‘Understand the Gap’.”

Heidi MacRae is a specialist GP in Auckland

Conflicts of interest: Dr MacRae has TNBC and self-funded Keytruda. She has supported the work of the Breast Cancer Foundation NZ and The Medicine Gap