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Triple-negative breast cancer: An overview for primary care
Triple-negative breast cancer: An overview for primary care
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Here at New Zealand Doctor Rata Aotearoa we are on our summer break! While we're gone, check out Summer Hiatus: Stories we think deserve to be read again! This article was first published on 6 July 2022.
By charting the experiences of a GP and a primary care leader who both became patients with triple-negative breast cancer, inequity in our health system is highlighted
- Breast cancer screening coverage rates have dropped off because of COVID-19. The Breast Cancer Foundation NZ estimates 50,000 women are behind on screening and, as a consequence, 300 women have missed having their breast cancer detected. Remind and encourage all your patients to have mammograms and examine women opportunistically. Remember, Māori and Pacific women are more likely to present late and experience worse outcomes, so make a point of encouraging them to get screened.
- You may be asked by the oncologist to prescribe a third primary dose of COVID-19 vaccine.
- During chemotherapy, admit a patient with a fever – febrile neutropaenia needs immediate investigation.
- Pembrolizumab causes autoimmune and endocrine side effects. Your patient will have their thyroid, cortisol and glucose monitored. If they get unwell, consider unusual issues such as a pneumonitis.
- Six months after chemotherapy, your patient will need to be revaccinated according to the Immunisation Advisory Centre protocols. They will also need live vaccines for measles and shingles, but that has to wait until six months after the pembrolizumab is finished.
- Following chemotherapy for breast cancer, immunosuppression can last up to nine months.
- Paclitaxel may cause lasting peripheral neuropathy in fingers and toes.
- There is a growing body of evidence that lifestyle measures can have a significant impact in reducing recurrence in TNBC. Women need to keep active, keep their weight healthy, avoid alcohol, reduce stress, stop smoking, reduce animal fat and increase consumption of fruits and vegetables.
- When it comes to counselling your patients about their breast cancer risk, it can be hard to advise them, and breast clinics are already inundated. A useful New Zealand-based online tool for women is BRRISK (brrisk.co). This costs the small sum of $35 and identifies those who need more proactive management – for example, those who are not eligible for a mammogram through BreastScreen Aotearoa (aged <45) who could be moderate or high risk following triage, those under age 50 who need annual breast screening because of their moderate risk, or those who need to go directly to a breast clinic because of their high risk.
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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
- By Fiona Thomson
I discovered a lump high up in my right breast quite by accident when applying some moisturiser. I have a history of breast cysts, and I’d had my routine mammogram within the previous 12 months, so I wasn’t immediately alarmed about the lump but knew it needed to be checked out. I contacted my GP (via patient portal) and asked her to refer me to our local radiology provider for a mammogram. The mammogram was followed by a biopsy and then an appointment with my GP for results.
By this stage, the breast cancer diagnosis was no surprise for me (you don’t make an appointment to see your GP for a “normal” result). When I first heard the term triple-negative breast cancer, my reaction was that anything “negative” surely had to be a good thing. How wrong could I be?!
I don’t recall much else from that consultation, other than the next step was referral to a breast surgeon at the hospital. I’ve spent the last 25 years in primary care management and consider myself a competent health system user, but I was in unchartered waters at this point.
As clinicians, you know the first thing your patient will likely do after a significant diagnosis is go home and consult with “Dr Google”, and I was no exception. Dr Google didn’t provide very encouraging information around TNBC, but what did strike me was that I was outside the risk profile – TNBC is more common in women under age 45, AfroCaribbean women and those with BRCA mutations. I am in my 60s, New Zealand European and have no family history of breast cancer.
Treatment plan options
By the time I finally saw the breast surgeon in the public system, about four and a half weeks had gone by, and the tumour appeared to be growing at an alarming rate. When I first felt it, it was about the size of apricot stone; by now, it felt more like the size of an avocado stone, and this was probably the scariest stage of my journey. I assumed my treatment would be mastectomy followed by chemotherapy.
The hospital-based breast surgeon and breast nurse were very informative. It was at this appointment that I learnt I was a candidate for neoadjuvant chemotherapy and would be referred to a medical oncologist. I couldn’t get an appointment to see the medical oncologist in the public system for another two weeks. Meanwhile, my tumour seemed to be growing by the day, and my husband and I made the decision to go private in an attempt to speed things up.
I went back to Dr Google to learn more about neoadjuvant chemotherapy and happened upon a summary of the clinical trial looking at the combination of neoadjuvant chemotherapy and immunotherapy for the treatment of TNBC.
My husband and I were in my (private) oncologist’s office within the week, and she laid out the neoadjuvant chemotherapy plan for us. Interestingly, it was me who raised the immunotherapy treatment option. She told us the clinical trial data had just been released and this was now considered the gold-standard treatment protocol for TNBC.
I already knew this was not Pharmac funded, but I found it interesting that the treatment plan with the best clinical outcome wasn’t the first one presented to us. It highlighted to me the difficult position clinicians are put in as a result of the inadequacy of Pharmac funding for modern life-saving (or quality of life-enhancing) drugs.
The treatment
My husband and I are in the fortunate position of being able to self-fund my treatment, so I was able to start the gold-standard TNBC treatment the next week (after insertion of a portacath in the public system).
The first treatment cycle was 12 weeks of chemotherapy (carboplatin plus paclitaxel weekly) and immunotherapy (pembrolizumab three weekly). I tolerated the weekly chemo well, and my hair fell out at exactly 21 days.
The second treatment cycle was 12 weeks of chemo (cyclophosphamide and doxorubicin three weekly) and immunotherapy (pembrolizumab three weekly). Doxorubicin really lived up to its nickname of “the red devil”, and this second cycle was certainly more challenging.
In the week following my first dose of doxorubicin, I was playing with our cat, and she nicked my right thumb pad with her claw. A seemingly innocuous scratch turned pearshaped very quickly – febrile neutropaenia and a three-day hospital stay in an isolation room on intravenous antibiotics.
I’m pleased to report that following chemo, my tumour had shrunk down to a size that was no longer discernible. I am now 30 weeks into treatment, and I have just had a hookwire-guided wide local excision and sentinel node biopsy.
I await the pathology results with fingers crossed it is a complete pathological response. Depending on results, I will undergo radiation therapy for anywhere between one and three weeks and commence oral chemo if I don’t get a CPR. My immunotherapy (pembrolizumab) will continue on a three-weekly cycle for the full 12-month period.
Things I learnt
When I first started my treatment plan, I was overwhelmed by all the treatment drugs, treatment pre-meds and post-treatment meds, and just trying to fit my husband’s and my life around the treatment programme. I ended up putting everything in chronological order in a spreadsheet so I could get my head around it (25 years of health manager coming out in me!). I found this particularly useful when I needed to interact with medical professionals other than those in my immediate care team (eg. hospital clinicians during my febrile neutropaenia episode).
All breast cancers are not equal – TNBCs are very aggressive and perhaps require more urgency around scheduling the appointments, procedures and consultations required before treatment.
Modern anti-nausea medications are very effective – use them liberally.
A positive attitude and a sense of humour around the side effects of treatment helps to mitigate any concern or awkwardness your family, friends and colleagues may have. I was open about my diagnosis and treatment so there were no surprises for those around me.
Oncology nurses are very special people.
“Chemo brain” really is a “thing” – worse than “baby brain” and “senior moments”. I managed to keep working through my treatment, but I wouldn’t advise this if (potentially impaired) decision-making has significant consequences.
We don’t talk about the important lifestyle factors that affect the incidence and mortality of cancer nearly enough, particularly alcohol. I was a regular drinker – a glass of wine most nights after work. Evidence suggests the risk of breast cancer for women increases by approximately 7–10 per cent per standard drink per day. I had no idea how much even moderate alcohol consumption was increasing my risk profile, and I firmly believe we need to increase awareness of the link between alcohol and breast (and bowel) cancer.
I was shocked to learn that New Zealand is at the bottom of the developed world for per-capita spend on modern medicines, such as pembrolizumab. Countries such as Mexico, Colombia, Latvia and Belarus are ahead of us. Being last doesn’t sit at all well with me. Women with TNBC and financial means can access a gold-standard, life-saving treatment programme, while those without financial means cannot – I’m incensed by the injustice of this.
I strongly support the work of Rachel Smalley and The Medicine Gap (themedicinegap.co.nz) in illustrating the extent of this problem. I urge clinicians and consumers alike to familiarise themselves with The Medicine Gap and advocate for adequate Pharmac funding to ensure equitable access to modern life-saving medicines for all New Zealanders.
Fiona Thomson is a former chief executive of General Practice NZ and current medical recruitment manager at Health Hawke’s Bay
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1. Breast Cancer Foundation NZ. 30,000 voices: Informing a better future for breast cancer in Aotearoa New Zealand. Auckland, NZ: Breast Cancer Foundation NZ; 2022.
2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382(9):810–21.
3. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 2022;386(6):556–67.
4. Pharmac Review. Interim Report. 20 December 2021. https://pharmacreview.health.govt.nz/interim-report
5. Te Aho o Te Kahu, Cancer Control Agency. Cancer Medicines Availability Analysis. https://teaho.govt.nz/reports/publications/cancer-medicines