Breast cancer arises from the lining of the milk ducts or from the lobules that produce milk. The early state of the disease is called ductal carcinoma in situ (or lobular carcinoma in situ) and is a pre-cancerous condition curable by local excision. In this condition, the cancer has arisen from the ductal cells which are ‘piling up’ in the ducts but the cancer has not penetrated the basement membrane which contains the ductal cells. Without penetration of that basement membrane, the cancer cells have no access to lymphatic or blood vessels (the method of spreading/metastasis) and hence this ‘pre-cancerous’ condition is curable by surgery that obtains clear margins around the disease.
Two sub-types of breast cancer are commonly recognised; ductal breast cancer which is the commonest form (75% of all cases) arising from the ductal cells and lobular cancer (10% of all cases) arising from the milk duct lobules. Rarer breast cancers include medullary cancer, colloid cancer, papillary cancer, mucinous cancer and cribiform cancer.
In addition to the description of the type of breast cancer, the pathologist can also provide a classification of aggressiveness (grade 1 to 3), the presence of hormone receptors and other molecular markers such as mutation of the oncogene HER2.
Causes of breast cancer
Many risk factors have been associated with breast cancer. These include age, race, previous benign breast disease, previous breast cancer diagnoses, lifestyle habits, reproductive factors, family history and genetic factors, exposure to radiation and environmental factors.
There is now good evidence for the involvement of female sex hormones in the incidence of breast cancer. The risk appears to be related to prolonged cumulative exposure of the milk duct cells to unopposed oestrogens. The rate of cancer rises gradually up to the age of 45 to 50, following which there is a less gradual rise up to the age of 75.
Benign breast disease can marginally increase the risk for breast cancer. Examples of these conditions include atypical lobular hyperplasia, atypical ductal hyperplasia and less so: fibroadenoma, intra-ductal papillomas.
A history of breast cancer in one breast can predispose to development of cancer in the other breast; this can be high for lobular cancer, (20-25%).
Lifestyle factors which may influence a patient’s reproductive history can impact on the development of the breast cancer. An early menarche, late first pregnancy, low parity and a late menopause all increase the risk of breast cancer in an individual woman.
A positive family history of breast cancer, particularly several first degree relatives developing the disease at an early age suggest the genetic origin, and this may account for perhaps up to 10% of all cases. Specific genetic mutations that predispose to breast cancer include BRCA1, BRCA2, P53, ATM, PTEN, PALB2, BRIP1 and others. Many of these are to do with a specific genetic fault in DNA repair.
Hormone replacement therapy has recently been the subject of a number of large studies. Long term use of hormone replacement therapy is associated with an increased risk of breast cancer when women were taking a combined preparation for up to five years. This has led to recommendations for more vigilant administration of hormone replacement therapy.
Patients previously exposed to ionising radiation such as survivors of the atom bomb or those patients treated to radiotherapy to the chest at a young age for a condition called Hodgkin’s lymphoma are at increased risk of breast cancer. There is no known link between breast cancer and low levels of radiation such as those used in imaging tests unless there is a possible genetic susceptibility to breast cancer.
One of the most interesting epidemiological features of breast cancer is the striking variation in incidence in different countries across the world. There is a five fold difference in incidence between the incidence in some western countries and low risk areas of the world (see main figure in the Incidence section). These differences cannot be entirely explained by differences in the genetic make up of the populations. For example, there is a striking difference between the incidences of breast cancer in the USA (high) versus Japan (low). This correlates with the differences in age at menarche and postmenopausal weight (heavier post menopausal women having higher serum levels of oestrogens circulating).
Where there is a strong family history in first degree relatives, there are now available tests for the oncogenes that have been found to predispose to this disease. The common ones to be responsible such familial breast cancer are the BRCA-1/ BRCA-2 and the PALB2 and BRIP1 genes and the routine testing for these genes in families with such strong incidences is something for which clinical geneticist counselling is now available. Young women with triple negative breast cancer (vide infra), should be tested for genetic predisposition genes even without a family history, as they too are more likely to carry such a genetic mutation.
Amongst patients with a strong family history of breast cancer, there have been several studies looking at the chances of a specific gene being at fault: The Breast Cancer Linkage Consortium recently published a study of 237 families with at least four cases of breast cancer within the family. They found that 52% of families were harbouring the BRCA 1 gene, 32% the BRCA 2 gene and 16% were due to some other genetic predisposition. Almost all families with breast and ovarian cancer represented within the family were associated with one of the BRCA genes (81% BRCA 1 and 14% BRCA 2 and only 5% unidentified). In families with one or more cases of male breast cancer (usually only 1% of the overall cases of breast cancer) there was a greater than 75% chance of the predisposing gene being BRCA 2 gene, which also seemed to be more likely to cause very large percentage of the risk (i.e. to be associated with 6 or more family members to be affected).
Whilst there are huge advantages to know that there is a genetic predisposition to developing breast cancer, there are also serious consequences of obtaining this knowledge: On the one hand the patient will know, if she tests positive, that she falls into a category of patient who is at very high risk of developing a breast cancer or ovarian cancer, or, if she has already had one breast cancer, that she is at an 85% risk of developing another and also of developing ovarian cancer and less commonly, other cancers. She will be advised to undergo rigorous screening and consideration of the whole issue of bilateral prophylactic mastectomies (and prophylactic removal ovaries) then comes into discussion. Next, patients have to consider the issues of having subsequent life insurance premiums loaded against them or mortgages etc – because for sure they will be required to disclose these results in the application forms in the future. Lastly, they have to consider that all these points will apply to their children. The medical discovery of genetic predisposition genes (oncogenes) and the knowledge by patients of their possession within their genetic code and the whole question of testing is a highly controversial and important one in breast cancer, and many other cancers at present.
Statistical models based on the above data have been researched to estimate a patient’s chance of having the BRCA 1 or 2 mutation based on their family and personal medical histories. Computer modelling estimates probabilities of breast cancer risk and one of these is now available via the internet: www.isds.duke.edu/~gp/brcapro.html. Whilst all such modelling contains flaws (biases due to selection) they give an overall band of risk category for patients which can then be further discussed with clinical geneticists if appropriate.
Approximately 25,000 women develop breast cancer annually in the UK. Many women still die from this disease each year in spite of increased cure rates over the last two decades. The age specific incidence rises by a factor four as the age rises from 35-70 years and by the age of 80 there is a 1/12 chance for women developing this disease. Male breast cancer counts for less than 1% of cases.
Many risk factors have been associated with breast cancer. These include age, race, previous benign breast disease, previous breast cancer diagnoses, lifestyle habits, reproductive factors, family history and genetic factors, exposure to radiation and environmental factors.
Breast cancer incidence rates, taken from a large database of American patients, suggests a decline over the last few years which may be linked to discontinuation of hormone replacement therapy.
Breast cancer incidence rates are highest in northern Europe and North America but the rates are rising in other countries suggesting a relationship to societal change.
Overall, death from breast cancer continues to decline and this is thought to be due to the early detection of breast cancer and the more widely available adjuvant early therapies consisting of surgery, radiotherapy, chemotherapy, hormone therapy and biological treatments.
Symptoms & diagnosis: Breast cancer
A proportion of women may not have any symptoms of breast cancer but detection is made via mammography. A patient may also note a lump in the breast that would require specialist assessment with appropriate tests to identify the nature of the lump.
Advanced cases of breast cancer can present with a larger lump, inversion of the nipple, involvement of the skin or bleeding. There may also be signs of spread of the breast cancer with swelling of the lymph glands under the arm pit or secondary tumours (metastases) that have spread to other sites. These may cause, for example, bone pains due to bone spread, general ill health or signs referable to the organ where the cancer has spread.
The biopsy or assessment of the sample cells is needed to confirm a diagnosis of breast cancer. Fine needle aspiration of cytology (FNAC) involves inserting a hollow needle into the abnormal breast lump and aspirating abnormal cells so that they can be analysed under the microscope. This can be performed either by Outpatients or using an ultrasound or mammography. If the cytology assessment confirms cancer then the patient proceeds to staging and appropriate therapy for their stage. There can be a non diagnostic result from FNAC and a formal surgical biopsy is then required of the abnormal area of the breast. The breast lump may require localisation by mammography and identification by a guide wire placed at mammography before a biopsy is attempted.
The treating oncologist will want to know whether the tumour is localised to the breast or whether it has spread to the local lymph nodes or whether it has spread to further afield.
Clinical examination supplemented by scanning will assist in this regard. Treatment is tailored to the extent of the disease at presentation.
Treatment and outcomes: Breast cancer
Pre Invasive Breast Cancer
If the result of a diagnostic assessment suggests a pre invasive cancer DCIS (ductal carcinoma in situ – i.e. it has not broken through the walls of the milk duct – and hence has no access to routes of spread) or LCIS (lobular carcinoma in situ), then surgery is the curative therapy of choice. This is a highly curable condition and treatment pre-empts the development of invasive cancer.
A mastectomy (removal of the whole breast) may need to be considered if the mammogram suggests widespread pre invasive cancer changes but , for small areas of in situ cancer, usually breast conserving surgery (lumpectomy or wide local excision) is enough. Following a mastectomy there is usually no further need for other therapy apart from standard surveillance, but after breast conserving therapy (particularly where the in situ cancer is close to margins or is large or multifocal (that is in more than one breast site) the Oncologist may often recommend post-operative radiotherapy to the breast. Where breast conserving surgery has taken place, post operative radiotherapy to the breast reduces the recurrence rate of DCIS and invasive breast cancer.
There is evidence demonstrating that anti-hormonal therapies such as tamoxifen further reduce the incidence of recurrent DCIS and reduce the development of invasive cancer in the involved and the contralateral breast – i.e. in the other breast.
Treatment of invasive breast cancer
Treatment should be discussed between the surgeon and oncologist (at a multidisciplinary meeting where imaging and pathology specialities are represented), as treatment may involve a multi modal approach including surgery, radiotherapy, chemotherapy, hormone therapy and biological treatments.
For all patients where the staging has demonstrated localised disease or disease confined to the breast and lymph nodes in the axilla, the commonest approach would be to consider surgery followed by a combination of chemotherapy, radiotherapy, hormone therapy and/or biological treatments. In certain patients, prior treatment with chemotherapy or hormone therapy may allow a reduction in the size of the tumour so that the surgeon can perform breast conserving surgery. The decision for radiotherapy, chemotherapy, hormone therapy and biological treatments would be based on certain characteristics of the tumour.
Apparently localised breast cancer (breast +/- axillary nodes only). We will now consider the different modalities individually and then discuss the decisions as to how to combine these optimally for individual patients
Surgery: The guiding principle of breast surgery is to achieve the removal of the tumour with clear margins (i.e. on histopathological analysis of the resected specimen there is no microscopic cancer reaching the resection margins). For small cancers, the operation of choice is ‘wide local excision’, alternatively called lumpectomy or quadrantectomy. The surgeon removes the tumour in toto with those clear margins. If followed by radiotherapy, such a breast conserving operation is as safe as a full mastectomy.
Where the cancer is large, primary chemotherapy (or endocrine/antihormonal therapy) might be used in the first instance to try to shrink the cancer such that a breast conserving operation may safely take place with those clear margins; this strategy has the added advantage of getting systemic therapy (therapy that goes all around the body) early in such a higher risk case – where preemptive prevention of metastatic spread is desirable.
A total mastectomy may be needed for multifocal cancer or where there is also widespread pre-cancer (in situ disease – vide supra).
Breast reconstruction will be later discussed with the patient. (A subcutaneous mastectomy is occasionally a safe method of preserving the skin and nipple of the breast for selected lower risk cases).
Surgery also plays an important role in the assessment of the lymph nodes in the axilla and sampling/removal of the ‘sentinel’ nodes (those nodes that drain the area of the breast from which the cancer arose) is part of the definitive breast operation. This gives the Oncologist important information relevant to risk of future relapse and the need for adjuvant therapies.
Where those nodes are heavily involved by cancer, the surgeon proceeeds to axillary node dissection (where he clears the axilla of nodes). Axillary dissection is now less commonly performed for lightly involved axillary nodes (e.g. micrometastatic disease in the nodes or only one macroscopic node metastasis) as the control of disease with modern adjuvant therapy has sufficiently lowered the risk of axillary relapse such that the risks of the full axillary dissection – such as arm swelling/oedema – do not justify this operation.
Radiotherapy plays a key role in the management of patients who have undergone breast conserving surgery.
Radiotherapy would also be considered as treatment to lymph nodes where there is a higher risk of recurrence.
Chemotherapy can provide substantial benefits to patients treated with curative intent.
Adjuvant chemotherapy refers to the administration of chemotherapy after the operation (even though there is no discernible disease) to reduce the chance of later relapse. This premise has been overwhelmingly proven in breast cancer to reduce the chance of later relapse and to bring increased cure rates in this disease. The selection of patients who will benefit from chemotherapy requires discussion. It is based of risk factors discernible from the presentation, the histopathology of the operation specimen and sometimes gene expression array data.
From the pathology report of the operation, the axillary node status (involved versus non-involved), the size and grade of the cancer, the oestrogen and progesterone expression status and the cerb-2/Her-2 amplification status of the cancer can be discerned and this in itself may be enough for the Oncologist to know if chemotherapy is required.
For example, in the case of a young woman who has a grade 3 ductal cancer of 2.5 cm diameter and multiple positive axillary lymph nodes for cancer, there is very strong evidence that his patient would have a significant risk reduction for future relapse by undegoing adjuvant chemotherapy. No extra tests are needed and the oestrogen receptor status would not influence the decision (although whether anti-hormonal adjuvant therapy follows the chemotherapy would indeed be influenced by the oestrogen receptor status).
The chemotherapy that the patient would receive would usually contain an anthracycline (doxorubicin or epirubicin), a taxane (paclitaxel/taxol or docetaxel/taxotere) and an alkylating agent (usually cyclophosphamide), and although inclusion of plains (cisplatin, carboplatin) have recently become a standard for Her-2 amplified and triple negative cancers, with anthracyclines (and 5-fluorouracil) taking more of a “back seat”. Triple negative cancer refers to tumours that are negative for ER, PR and Her-2. The drugs are injected intravenously every three weeks (as this allows time for the bone marrow to recover from the previous course) and between six and eight course of chemotherapy are delivered. (Sometimes taxol is given weekly). The side effects of chemotherapy include nausea (for which modern anti-sickness treatments are highly effective), hair loss (which should be fully reversible) and low blood counts (from days six to sixteen after chemotherapy – which is why the drugs are recycled at three weekly intervals). During the period that the blood count – in particular the white cells which fight infection – are low, the patient is at risk of infection and any high fevers need hospital attention. Chemotherapy, particularly with the inclusion of alkylating agents may bring forward the menopause – the more likely in 40+ year olds than 30 year olds.
If the patient’s cancer had over-expression (amplification) of Her-2 oncogene then the adjuvant chemotherapy would include two important drugs: Trastuzumab and pertuzumab – important inhibitors of the downstream effector pathway of the stimulating growth effects of the mutated Her-2 gene. Trastuzumab/pertuzumab is usually partnered with taxane chemotherapy and given at three weekly intervals +/- other chemotherapy; however, its administration continues after the cheotherapy is finished out to one year (cardiac monitoring is performed as there are cumulative small risks to cardiac function). The use of Her-2 directed therapy in this manner has been shown to highly significantly reduce the later relapse risk in this higher risk subgroup of breast cancer patients, which comprises approximately 20% of all breast cancer cases.
Many cases are not so straightforward in assessing the need/benefit of adjuvant chemotherapy and this is a major issue for the patient and her Oncologist viz. to advise the patient whether there is a sufficient risk reduction following chemotherapy for her to accept this, particularly bearing in mind the side effects. For example, as we shall see below, much benefit accrues from anti-hormonal adjuvant therapy in oestrogen receptor positive cancers and there is no doubt that in some strongly oestrogen receptor expressing cancers (so-called ‘luminal A subtype’) that antihormonal drugs may convey almost all of the benefit from adjuvant therapy and chemotherapy adds insignificantly to the risk reduction.
There have evolved many predictive tests/analyses, largely based on the genomics of the tumour supplemented by the known prognostic factors such as node status, oestrogen receptor status, size of the cancer, age of the patient etc and based on a very large bank of prognostic variables that have been retrospectively studied in thousands of patients who have and have not relapsed over time – to create advice to Oncologists over the risk reduction (quae later relapse) afforded by chemotherapy. We will now consider one important publication from 2018 which has settled the matter for at least one group of patients with this dilemma.
In this study (New England Journal Vol 397, pages 111-121) the authors studied 10,273 women with oestrogen receptor positive, Her-2 negative (non-amplified) and axillary node negative breast cancer to probe as to whether adjuvant chemotherapy followed by adjuvant anti-hormonal therapy provided better protection against later relapse than adjuvant anti-hormonal therapy alone. They used a gene expression profile of 21 genes to develop a risk score for later relapse. Patients with a score of 1-11 had a very low risk of relapse and would not benefit from chemotherapy and this group would not have been offered this anyway. However, the interesting group in this Oncotype DX analysis was those at an intermediate risk of later relapse – they had scores of 11-25. Then there was the higher risk group with scores of >25 for whom we already knew would benefit significantly from adjuvant chemotherapy. SO: it was this difficult intermediate group of patient for which this important study really sought to answer the question as to what extra did chemotherapy do.
The analysis showed that, overall, that intermediate group of patients with scores of 11-25 did not gain extra benefit from the use of chemotherapy in addition to anti-hormonal therapy – a very important discovery that has changed practice in this large group of women. There is one caveat that in young women wit h scores of 16-25, there was some benefit from chemotherapy in addition to anti-hormonal therapy and so in this subgroup the practice will probably continue. This study has been followed by other predictive algorithms, based on clinical staging, age, tumour characteristics and genomics (again largely based on on oestrogen expression and proliferation genes) that are applicable to calculating the survival improvement for node positive patients (e.g. Endopredict test).
Adjuvant anti-hormonal therapy
The way that oestrogens stimulate their target tissues is via the oestrogen receptor (ER).
At puberty, the ‘awakening’ ovaries secrete oestrogen into the circulation and this is picked up by the infantile breast milk-duct epithelial cells where the oestradiol/ER complex effects the stimulatory role that leads to breast development. The complex is formed in the cytoplasm of the cell but the complex moves to the nucleus where it binds to specific regions of DNA to effect its function.
The “better behaved”, well-differentiated (meaning that the cancer cells under the microscope look somewhat like the normal breast tissue) breast cancers are usually the ones that express ER richly.
ER+ or oestrogen receptor positive breast cancers are those that express the oestrogen receptor – a 7Svedberg (7S) cytoplasmic protein to which oestradiol binds avidly and the complex gets transported to the nucleus of the cell where it binds to specific regions of DNA to effect largely stimulatory functions to do with growth and development.
The gene that codes for the ER is called ESR2.
There are two recognised subtypes of the ER (alpha and beta) and different oestrogen tissues express the two subtypes in different proportions – a point to which we will return below.
Just as we referred to the term: ‘adjuvant therapy’ for chemotherapy used in this situation, so the term: adjuvant anti-hormonal therapy is used when this type of therapy is given, after a potentially curative operation, once again used to reduce the risk of any subsequent relapse.
The aim of hormonal therapy is to minimise exposure of a potential cancer cell to oestrogen or antagonise the oestrogen receptor.
The available drugs can achieve this by different mechanisms.
Tamoxifen is an antagonist at the ER and has a long pedigree is treating ER+ breast cancer. It has been known for 30 years that administration after operation for early ER+ breast cancer (i.e. adjuvantly) reduces the future risk of breast cancer relapse. Up until recently the evidence was in favour of its administration for five years after the operation but recently there has been demonstrated that the advantage of adjuvant tamoxifen extends out to ten years but only for those with node positive tumours at presentation. Axillary node negative patients are not so advantaged for adjuvant hormonal therapy beyond five years.
Although we will discuss below the optimal use of anti-hormonal drugs in pre- versus post-menopausal women, nevertheless, tamoxifen is active in both pre- and postmenopausal women with breast cancer (ER+) – the ER/tamoxifen complex having direct anti-cancer effects in the cell nucleus even in the low oestrogen environment of the post-menopausal woman.
There are other oestrogen receptor modulators – called SERMS – (with varying differential effects on the alpha and beta subtypes of ER) but tamoxifen retains the prime position as the best drug-of-class for treatment of breast cancer.
With regard to different effects on alpha versus beta ER effects, tamoxifen – an antagonist in breast target tissue, can be a stimulant in other target tissues such as the uterus (where it can cause overgrowth of the endometrium – lining of the uterus).
Other side effects of tamoxifen include menopausal flushes. Interestingly, tamoxifen has a generally beneficial effect on blood lipid levels and paradoxically, for an anti-oestrogen, preserves bone density.
Adjuvant tamoxifen is the drug of choice for adjuvant therapy of early ER+ breast cancer (if ovarian suppression is not recommended – vide infra).
The interesting drug fulvestrant is another type of oestrogen antagonist – binding avidly to the ER and down-regulating the ER. However, its use is mainly in the advanced disease setting and not adjuvantly – vide infra.
Aromatase inhibitors (Anastrazole, Letrozole, Exemestane) work in a different way to reduce the oestrogen levels in the postmenopausal woman. Whilst (without functioning ovaries) the level of circulating oestrogen is much lower in the post-menopausal woman, nevertheless, there is enough oestrogen to have a stimulatory effect on ER+ breast cancer – particularly given that it is synthesised within the oestrogen target tissue cells themselves from the lowest levels of circulating adrenal steroids.
The adrenal glands secrete C-19 steroids and oestrogen target tissues (and ER+ breast cancer cells) contain an enzyme : Aromatase’ which converts these C-19 steroids into C-21 oestrogens.
Aromatase inhibitors have been shown to be a slightly better (in terms of risk reduction quae relapse) adjuvant anti-hormonal therapy than tamoxifen in very large head-to-head trial, in post-menopausal breast cancer, and it is now standard practice to place a lady with early ER+ breast cancer on a drug such as letrozole (2.5mg oral daily) as adjuvant anti-homonal therapy after her operation for early ER+ disease, and for 5-10 years, the latter for node positive disease. The patient may get a slight exacerbation of menopausal symptoms, some muscular/joint stiffness/pains and, in the long run, some thinning of the bones (osteopenia or osteoporosis) – for which she should be monitored. The fasting cholesterol may increase relevantly.
In general, any adjuvant chemotherapy is delivered prior to starting any anti-hormonal therapy.
The aromatase inhibitors do not work if the ovaries are still actively secreting oestrogens (i.e. in the pre-menopausal state).
The biggest recent contreversy with regard to adjuvant anti-hormonal therapy for early, ER+ breast cancer has recently been as to whether all pre-menopausal women with invasive ER+ breast cancer should have ovarian ablation or suppression rather than anti-hormonal therapy as a recent trial has shown superiority for the ovarian suppression plus anti-hormonal drugs. The use of the aromatase inhibitor: exemestane as that anti-hormonal drug, rather than tamoxifen in the group that underwent ovarian suppression proved better than tamoxifen. Having said this, there were much more side effects in women who had the ovarian suppression plus drug – largely due to the abrupt menopause and immediate introduction of an oestrogen inhibitor or suppressant. Therefore the Oncology profession is grappling with the risk category of patient for whom the ovarian suppression should always be recommended. At present, we use the Oncotype Dx test to decide whether ovarian suppression plus an aromatase inhibitor, or tamoxifen is used – the latter for low risk patients. Where chemotherapy has been used, a high risk group, ovarian suppression plus an aromatase inhibitor is used; sometimes the chemotherapy itself will have effected the menopausal state. Measurement of serum FSH/oestradiol determines whether this is so.
Such adjuvant anti-hormonal therapy and go on even in Her-2 patients who are going on with their adjuvant herceptin
In patients who are at high enough risk to require adjuvant chemotherapy, and whose ovarian function survives that chemotherapy (for often the chemotherapy brings forward the menopause) there is good reason now to always recommend ovarian suppression and anti-hormonal drug therapy.
In general, a single drug or a combination would be recommended for a minimum period of five years. Sometimes, the treating oncologist will recommend a younger lady to have ovarian suppresion.
Systemic therapy for advanced breast cancer
The optimal treatment for patients presenting with advanced breast cancer (whether regionally in the breast/axilla or those with distant metastatic spread) is based on systemic therapy – that is therapy that goes all around the body.
Systemic therapies to be discussed include the anti-hormonal therapies (and Smart drugs that augment or are active in patients with ER+ disease resistant to standard anti-oestrogens (whether tamoxifen, fulvestrant or aromatase inhibitors) – e.g. cyclin dependent Kinase 4/6 inhibitors, m-Tor inhibitors and PI3 kinase inhibitors to name three.
If a patient presents with disease that has spread beyond the breast, then the emphasis of primary management will be on systemic therapy (i.e. therapy that goes around the whole body (perhaps with less brain penetration) not only to treat what is known to have spread but also nascent metastatic disease.. This therefore requires chemotherapy, anti-hormonal therapy or/and smart drug therapy.
The way the Oncologist plans best treatment is based on the following:
If the disease is not imminently life threatening and the patient has ER+ (and Her-2 non-amplified) breast cancer then there are good data to support primary anti-hormonal therapy (ovarian suppression with an aromatase inhibitor in pre-menopausal patients and an aromatase inhibitor in post-menopausal patients) combined with a cyclin inhibitor such as palbociclib. The response rate is high and the addition of the palbociclib (or another: ribociclib, abemaciclib) doubled the progression-free period in one large trial over the aromatase therapy alone in such patients with metastatic disease. Resistance to aromatase inhibitors is often correlated with ESR mutation and fulvestrant plus a MAPK pathway inhibitor e.g. everolimus, PI3K inhibitor – can cause another remission before needing to fall back on chemotherapy.
If the advanced breast cancer is imminently threatening – e.g. fast growing disease in the breast, axilla and particularly in the organs such as liver and lungs, then the Oncologist will first advise chemotherapy. Almost irrespective of the ER status (i.e. positive or negative) fast growing and life-threatening disease is usually first treated with chemotherapy – keeping the anti-hormonal therapy as maintenance therapy after the chemotherapy course is over and in ER+ disease.
The choice of drugs mirrors that described in the adjuvant chemotherapy section above but there are some new considerations.
In patients with triple negative disease (i.e. ER- , PR – and Her-2 non-amplified) and particularly where they have had prior chemotherapy with the drugs mentioned above and in the not too distant past, then this group of patients may respond well to the platin chemotherapy: cis-platin and carboplatin.
For patients whose breast cancers occur due the inheritance of the BRCA mutation and also for triple negative breast cancer – which is often BRCA-like , there is a deficiency in DNA repair pathways and the combination of a platin based chemotherapy regime, enhanced by a PARP inhibitor [Poly ADP Ribose Polymerase inhibitor] such as olaparib, which potentiates the DNA repair fault that has already been exposed by the platin – thus the combination of this smart drug and the platin leads to greater cancer cell death. Our own experience is that the blood count suffers if the PARP inhibitor (a simple oral drug) is taken daily throughout the therapy course and we now concentrate the administration around the time of the platin chemotherapy or give the drugs sequentially rather than together – this licence is for sequential therapy.
For advanced breast cancer that relapses soon after the adjuvant chemotherapy outlined in the adjuvant section, the chance of those same chemotherapy agents bringing about a good and durable remission is fairly low and alternative chemotherapy agents would be trialled. The platins might be trialled and the combination of a platin with gemicitabine is a popular regime at present (I have commented above on triple negative and Her-2 + disease). Other drugs that are used as single agents or in combination include eribulin, methotrexate with 5-fluorouracil and cyclophosphamide (in a regime called CMF – which was the first really effective combination chemothepy ever introduced for breast cancer). Weekly taxol (sometimes combined with the Smart drug: Trastuzumab/Avastin is also popular despite chequered reporting for avastin in this disease. Always the drug is given for several courses and repeat scans a re compared with baseline ones to assess efficacy.
If the clinician wants to know as soon as possible if the disease is responding to therapy then cell-free DNA (cfDNA) quantitation (as the tumour is shedding its DNA into the blood stream all time) is quicker method assessing response if the cancer is releasing adequaately. The blood cancer markers: CEA and CA 153 may also help in the assessment of early response.
Where a long interval has elapsed since adjuvant therapy, using the drugs outlined above in the adjuvant chemotherapy section, then it is worthwhile re-challenging the patient with those front-line agents again.
Usually, the chemotherapy takes about three to four months (six to eight courses). The role of capecitabine as subsequent maintenance therapy has some validity but risks prejudicing the bone marrow reserve for later stronger intravenous therapy. We use it for unstable remissions following the intravenous front-line chemotherapy – particularly in triple negative disease.
Where the patient has presented with advanced breast cancer that is Her-2 amplified, then the addition of the Smart drugs Trastuzumab and pertuzumab are important. Pertuzumab enhances the response rate and duration of remission further when combined with trastuzumab. The drug Taxotere or taxol usually partners the drug combination of Trastuzumab and Pertuzumab. Where there is brain metastatic disease, the orally active Her-2 directed therapy: lapatinib or more recently Neratinib or Tucatinib (both small molecules that cross the blood brain barrier) are used – as they has better brain penetration; it is often combined with capecitabine (a drug related to 5-fluorouracil). A combination drug: Ado-trastuzumab (Trastuzumab/emtansine) is a hybrid drug combining the trastuzumab and a chemotherapy drug in one molecule it is currently used for Her-2 positive disease treated primarily with neoadjuvant chemotherapy plus trastuzumab/pertuzumab and yet the surgical specimen still shows viable disease.
It is important to monitor cardiac function in patients on prolonged course trastuzumab/pertuzumab as there have been reports of cardiac failure after high cumulative doses.
When chemotherapy is finished, the patient has a new baseline scan and cancer markers assessed and this forms the new baseline against which all subsequent assessments are compared at intervals of follow-up. In ER+ disease then the patient is put on appropriate anti-hormonal therapy.
In patients with one or perhaps two sites of residual disease at the end of chemotherapy, particularly if there were only these sites of disease at the beginning of the course (in more gross extent), then this is considered as oligo-metastatic disease and we consider if focal therapy to this residual disease is warranted (i.e in the patient’s interest – to prolong the remission). Thus , if there is just one liver metastasis, or one bone metastasis remaining on the end-of-therapy we would consider surgery, focal radiation ablation (Cyberknife – or Gamma knife if the residuum is in the brain) or radiofrequency ablation.
Radotherapy as a focal therapy for oligometastatic disease or a ‘trouble spot’ – usually a bone site that is not responding to systemic therapy as well as the other sites of metastatic disease – has an important role.
Sometimes highly focal radiation therapy (Gamma knife – for brain metastases or Cyberknife for brain or body focal metastatic sites (in small numbers) is used, having the perceived advantage of delivering a higher dose on the site of persistent disease than more conventional radiotherapy and a higher expectation of obliterating all viable cancer in that site. It should be noted that these highly focal therapies are not always appropriate – particularly if the lesions are large or multiple.
Brain metastases: these are an increasing problem nowadays with the improvements in systemic therapies (as the blood-brain barrier prevents the good access to the brain (and eye) of many drugs. Also, some sub-types of breast caner (particularly triple negative and Her-2 + breast cancer have a high proclivity for spreading to the brain. When the brain metastasis is single and less than 3cm diameter and not situated immediately adjacent to some critical radiosensitive structure such as the optic apparatus, then the focal radiation therapy methods of Gamma Knife and Cyberknife have an important role as they deliver obliterative doses to the brain metastasis and, because of the very fast dose fall-off (dose gradient) at the margins of the target (the metastasis), they can obliterate any viable cancer without high risk to adjacent structures.
Where there a two or three such metastases(or up to 20+ very small metastases), then these techniques are also very good therapies as they save operations needing surgery/craniotomies at several sites to reach metastases in different brain locations. However, for large metastases or those causing raised intracranal pressure, then surgery is the treastment of choice, with Gamma Knife or Cyberknife for any residuum or any other smaller metastases.
Where the metastases to brain are extensive, or where the meninges are involved (a highly dangerous condition called: carcinomatous meningitis) then wide field brain radiotherapy – fractionated over one to three weeks – is recommended.
Bisphosphonates are a class of drugs that are aimed at stabilisation of the bone architecture. Denosumab is another bone stabiliser (a Rankel inhibitor). Both these drugs delay progress or metastatic breast cancer into and in bone and are indicated in those with bone metastases (and perhaps preventitively)- during and after the chemotherapy. There is one odd side effect of these drugs, viz. a tendency to cause bone necrosis of the mandible in those with caries or other dental problems – e.g. root canal infection; both drug types are contra-indicated in this situation. Data are now available suggesting that bisphosphonates, administered to post-menopausal women with breast cancer, reduce the relapse rate by circa 1%, as well as maintaining bone strength.
The question then arises as to what happens if the patient relapses despite all the foregoing?
Well: there needs to be full re-assessment of the cancer and this is where modern genomics and consideration of immunotherapy comes in. We would recommend that the cancer is re-biopsied or, alternatively, cell-free DNA is examined (a simple blood draw) – both for next generation sequencing. Sometimes, there are genomic drivers that are activated that allow the cancer to escape from the foregoing therapies and for example the ‘escape’ via the PI3Kinase path. We now are often able to detect whether this escape route is in operation from cell-free DNA studies, which give a ‘mean’ of the tumour genomics and are not at the mercy of a single site tissue biopsy.
By following the genomic evolution of the cancer with serial cell-free DNA studies on the cancer through therapeutic endeavours, the emergence of escape mutational pathways in activating oncogenes allow us sometimes (not always) to pick up new escape clones of cells and bring in new therapies -directed towards that oncogene – in 2018 there is a new PI3 Kinase inhibitor.
So: for the patient who relapses through the best standard therapies, the best hope is next generation sequencing of the cancer – either by new tissue biopsy or cell free DNA sampling from the blood. The genomics of the cancer tells us how it is mutating and escaping from the standard therapies. It is in the enduring nature of a cancer to mutate and the ‘pressure of effective therapy for the cancer’ actually promotes mutations that enhance the cancer’s chance of continuing its growth “bypassing” the therapy that the patient is, at that time, taking.
cf-DNA has the advantage that one is looking at the mean of the tumour’s genomics and one is not at the mercy of a single site biopsy that may not be representative of the cancer as a whole. The author has a patient upon whom he has taken 14 samples of cf-DNA over several years to follow the genomic evolution of the cancer. (Not all cancers give enough cf-DNA into the blood for such cf-DNA analyses to be reliable). Circulating tumour cell genomics may be more relevant to the genomics (for targeted therapy) of the advancing cancer.
Now: immunotherapy has made big inroads into the successful therapy of some cancers in recent years – for example: lung cancer, melanoma and kidney cancer. So far, such success has not been achieved in breast cancer. However, it has been shown that triple negative breast cancer, which is a poorly differentiated cancer with hypermutation (i.e lots of mutations – which make it antigenic and hence prone to immune attack) is one subtype of breast cancer that is responsive to immunotherapy. Early studies with checkpoint inhibitors such as pembrolizumab and nivolumab have shown promise in this particular group of patients – in combination with chemotherapy (particularly platen-based chemotherapy).
Credit: Dr. P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH (AdvancedGenomics). tel: +44-207-6311632
Patients presenting with early breast cancer normally never relapse; a woman presenting with a small primary breast cancer which is node negative at surgery has a five to ten year chance of remaining free of disease of more 85%.
Conversely, if the patient presents with involvement of the axillary nodes, where they will have a 70% chance of relapse by five years, but reduced considerably by modern adjuvant therapy (vide supra).
Once the disease has spread to other sites, the chance of cure is slim, although we treat the patient with one apparent site of metastatic disease aggressively in the hope of cure – for example, for a patient who would be curable but for the discovery, on staging, of a single bone metastasis, one would treat with full adjuvant systemic therapy and add focal therapy (e.g.Cyberknife) to that bone lesion at the end of the systemic programme.
In the United Kingdom, a mammographic screening programme is available on the background of several trials demonstrating a significant reduction in mortality for those women who have received mammographic screening. There is a drive for educating women on self-assessment.
Genetic screening should be considered in those patients with a known family history, and young sufferers.
MRI imaging is a form of breast screening that is preferred to mammography in certain groups -e.g. the young woman who received prior radiotherapy to the chest (e.g. for Hodgkin’s lymphoma) in childhood
In general, the mammographic UK screening programme offers three yearly assessments for women aged 50-64. It is predicted that 70% of all new cancers will be detected at this stage that are impalpable or small. For specific patients the interval screening programme may be reduced.