Breast cancer and survivorship

by Dr Alison Louise Jones (pictured) – The headline figures are that the majority of women survive a diagnosis of breast cancer: 78% of those women currently diagnosed will be alive at 5 years and many of them will become long-term survivors. This is largely a consequence of improved treatment and in particular the increased uptake of adjuvant systemic treatment, both endocrine treatment and chemotherapy, and more recently specific targeted therapy such as monoclonal antibodies e.g. trastuzumab. But what happens to these survivors in terms of medium- and long-term health both physical and psychological, and who should these women be followed up by?

These best recognised sequelae of adjuvant treatment for breast cancer are related to induction of early menopause and exacerbation of menopausal symptoms.  The likelihood of menopause with chemotherapy is largely related to the age at which the woman is treated.  For example, at the age of 40 years approximately 70% of women will experience an early menopause either during or within 12 months of chemotherapy. This may be associated with short and medium-term problems including vasomotor symptoms (hot flushes) and gynaecological problems such as vaginal dryness and dyspareunia. There is no consensus as to the best management of vasomotor symptoms. It is accepted that oestrogen replacement is the most effective treatment for vasomotor symptoms however this is usually contraindicated with women with breast cancer especially in those with hormone receptor positive breast cancer. Other options include serotonin re-uptake inhibitors and gabapentin which have been shown to be effective although concerns have been raised about some serotonin receptor uptake inhibitors and their possible effect on tamoxifen metabolism. Vaginal dryness may be managed with simple lubricants although again local oestrogen replacement is the most effective. This is a reasonable option for women who are not on endocrine treatment or those women on tamoxifen, but there is concern that systemic absorption of vaginal oestrogen may be a problem in terms of raising oestrogen levels in women on aromatase inhibitor adjuvant therapy.

The main concern for medium- to long-term survivorship is bone mineral density.  Women undergoing chemotherapy do experience an acute fall in bone mineral density while on treatment. The use of endocrine treatment with aromatase inhibitors may exacerbate bone mineral loss. For women receiving drugs such as tamoxifen which is a selective oestrogen receptor modulator problems of bone loss are less and indeed tamoxifen has a relative protective effect on bone because of its oestrogen agonist activity. Increasing numbers of women who are post-menopausal receive aromatase inhibitor therapy and these women should have a baseline bone mineral density and need a clear pathway defined between primary and secondary care for identification of at risk women and appropriate monitoring and treatment.

The impact of chemotherapy may also have effects on ovarian reserve in pre-menopausal women and all women will experience some loss of ovarian function.  This may result in infertility especially for women in their 30s or early 40s. Those women who have oestrogen receptor positive breast cancer have an additional problem in that they will require 5 years’ of endocrine treatment and by the time they have completed adjuvant therapy their natural fertility will have declined further.  Given the demographics of childbearing behaviour in the United Kingdom and the increased proportion of first and subsequent pregnancies after the age of 30, this becomes a real issue for many younger women with breast cancer. It is possible to consider the use of GnRH analogues as ovarian protectants although the data are limited.  The most effective method of preserving fertility is the use of embryo cryopreservation however there are limited data on safety of this long term. It is reassuring however that the small number of women who have had breast cancer who subsequently become pregnant (approximately 7%) have no evidence of any adverse outcome in terms of their own risk relapse and mortality.

Women undergoing adjuvant treatment for breast cancer may also experience emotional sequelae and about 30% will have a degree of recognisable anxiety/depression within 12 months of diagnosis. The drive in secondary care to reduce follow up means that such women will need access to support either through a breast cancer specialist nurse or through primary care. The issues of cognitive impairment are also important and may be related to the use of adjuvant chemotherapy.  Impairment of cognitive function and fatigue (commonly associated with chemotherapy) can have a negative impact on return to work and activities of daily living. There is a need for research into the causes and risk factors for these problems and to methods of prevention and improvement.

Anthracycline chemotherapy such as doxorubicin and epirubicin regimens are the backbone of many adjuvant treatments.  These drugs are known to cause cumulative dose related cardiotoxicity which may result in impaired left ventricular function and in some cases cardiac failure. There is almost certainly a degree of myocardial loss for all women but this may not be problematic at time of diagnosis or indeed in the few years following diagnosis. As more women become survivors and develop health-related problems and co-morbidities associated with aging such as hypertension, such women may be at higher risk of late cardiotoxicity.  It has indeed been shown that mortality from cardiac causes is higher in breast cancer survivors compared with the age matched female population. These women are no longer on follow up at breast clinics and may require a “flagging” system for follow up in primary care or re-referral to a cardiac unit at a specified time point.

Newer drugs such as the Taxanes are increasingly used in adjuvant treatment.  We recognise their risk of side effects such as neuropathy which is mainly during or shortly after treatment and is thought to improve with time. There are little data on long-term neuropathic problems which may be worse in patients who have risk factures such as diabetes. Again this raises the question of how we detect long term toxicity in patients and who should be looking out for them. Furthermore, it may be possible to identify patients at risk of specific toxicities such as, cardiotoxicity or neuropathy using pharmacogenomic profiling of the patient. This would provide the potential for developing clinical trials to evaluate regimens that are not only “personalised” for the tumour but also personalised to the patient according to their individual risk of specific toxicity. This would be a truly personalised approach.

Success of cancer treatment is to be commended.  It is important however that we are cognizant that the treatment we offer may not be risk-free and that for survival other long-term side effects may be important both at an individual level and in terms of public health for a population. Strategies for follow up and identification of these patients are urgently needed.