Treatment of breast cancer

Starting with the earliest form of the disease, there is no doubt that wide surgical excision of areas of precancerous Ductal In Situ cancer (DCIS or preinvasive ductal cancer) or Lobular Cancer In Situ cancer (LCIS - preinvasive lobular cancer)is the curative therapy of choice. Sometimes the mammogram shows widespread intraductal disease and so total mastectomy (the removal of the whole breast) is required even for this pre-cancer. After total mastectomy has achieved clear margins, there is usually no further need for other therapy apart from a careful follow-up screening programme. Where breast conserving surgery has been employed, the use of post-operative ardiotherapy to the breast reduces the recurrence rates of DCIS and invasive breast cancer considerably.

 

Tamoxifen has also been demonstrated to reduce the incidence of recurrent DCIS

 

Before coming to the treatment of the invasive cancers, mention should be made of preventive therapy - particularly in this developing age of better understanding of enhanced genetic risks. In the 'Causes' section of this site, the familial/genetic predisposition to breast cancer has been discussed and this brings with it the possibility to prevent the disease in the first place. Such prophylactic therapy nowadays deserves discussion here: Firstly, any patient who develops a primary breast cancer is at some enhanced risk of developing another primary breast cancer over the background population: the risk being somewhere between 1%/year for sporadic (i.e no clear genetic/familial trait) patients to 2.5%/year for sporadic lobular cancer cases or 85% lifetime risk in BRCA genetic/familial cases (who also may have an enhanced risk of developing ovarian cancer). These facts plead strongly for a meticulous screening programme(usually mammographic follow-up , supplemented by ultrasound or MR in some e.g. lobular cancer patients) in all patients. In addition, many with very high risk of developing the disease (BRCA family members) may well opt, after careful clinical discussion with expert physicians, to undergo prophylactic ('insurance policy') mastectomy/ies (i.e removal of one or both breasts - usually followed by an immediate reconstruction operation). Those at high risk of ovarian cancer (or prostate cancer in males harbouring the BRCA 2 gene) should also undergo screening and women may opt for prophylactic oophorectomies (removal of both ovaries) if they are at high genetically determined risk of the disease by virtue of BRCA gene possession - usually after they have had their families and are approaching the natural menopause.

 

Also noteworthy are the results of trials demonstrating the efficacy of tamoxifen in the prevention of breast cancer development in both sporadic and familial breast cancer. The use of tamoxifen after the development of breast cancer, to reduce the risk of later relapse/metastases, is well established but the use of this drug, taken to prevent the development of the disease ab initio, is a relatively new concept, (and one that must be discussed in the context of the known side effects of tamoxifen, as here the drug is being given to a healthy person who has not developed the disease).

 

 

Small primary invasive cancers in the breast (say up to 3 cm or so in diameter) can be treated by breast conserving surgery – the operation being called: lumpectomy, segmental mastectomy, quadrantectomy, wide local excision etc.- all these operations having in common the ability to preserve the breast in a reasonable cosmetic form. However, for this option of breast conservation to be a reasonable and acceptable (i.e. as safe as a total mastectomy) then certain eventualities must apply. The first is that the surgeon achieves a margin of uninvolved normal breast tissue around the tumour that he has excised. If he does not achieve such a margin at the first ‘lumpectomy’ then he may try again by a wider excision or go for total mastectomy, but one way or another he should have achieved microscopically ‘clear’ margins at the end of his operation(s) – and this includes the margins being clear of DCIS/LCIS (which so often surrounds the invasive cancer).

 

The second prerequisite for safe breast conserving surgery is that the patient undergoes post-operative radiotherapy to the breast. It has been shown that the breast conservation surgical approach is only as safe as total mastectomy in this situation if followed by radiotherapy. (For very small cancers, say of 2mm diameter and the screening programme is now throwing up such cases more and more often - sometimes as an incidental early cancer detected by the pathologist within an area of DCIS – it may be safe to withhold post-operative radiation therapy. This is still under trial and the standard wisdom remains that post-operative radiotherapy is always required, except perhaps in the very elderly where tamoxifen may be an acceptable alternative.

 

Lastly, it is clear that the use of breast conserving surgery should not be extended for more advanced cancers, e.g. those involving the skin or tethered to the underlying pectoral muscle. Total mastectomy has long been the gold standard operation and usually is performed without the removal of the pectoralis muscle nowadays. It may still be indicated for early tumours such as those involving the central breast/nipple for whom a good cosmetic result may be impossible. In these patients then total mastectomy with subsequent reconstruction may be best and this has also been mentioned as being necessary for widespread breast involvement by DCIS/LCIS.

 

The practice of subcutaneous mastectomy (the removal of the functioning breast unit, i.e. the ductal system from which the breast cancer arises) together with immediate reconstruction is now practised widely and leaves a good cosmetic result as the patient keeps her normal breast skin and nipple and the main body of the breast is substituted under the skin. Once again it is important that the surgeon does not extend his indications for this practice beyond early disease as to do so prejudices local control of more advanced cancer within the breast region, which is more difficult to follow-up by screening mammography when a ‘substituting’ prosthesis is in place.

 

The next area of surgical decision making is as to what surgery to perform in the axilla/armpit. The rationale for removing at least some of the axillary lymph nodes is that the detection of involvement, under the microscope, of the nodes by the cancer is an immediate predictor of high risk for subsequent relapse and one indicator that the treating doctor will consider before recommending that ‘insurance policy’ chemotherapy or hormone therapy should be given at this early time point.

 

It was established beyond doubt some twenty years ago that the delivery of chemotherapy to young patients with cancer apparently localised to the breast, but whose axillary nodes were positive under the microscope for cancer cells, reduced the risk of the patients subsequently relapsing and dying from the disease. These higher risk patients were unequivocally protected from subsequent relapse and death by this therapy. Of course, not all the patients needed the therapy but statistically such chemotherapy reduced the risks in this group and as it was not possible to detect those in definite need, so it became standard practice to deliver chemotherapy ‘up front’ (medically referred to as: adjuvant therapy) to all node positive young patients after the operation.

 

In the years that have elapsed since these facts were established, it has become clear that one can detect other groups of breast cancer patients who will so benefit from adjuvant therapy with chemotherapy: patients with large tumours, tumours with intermediate sized tumours (e.g. 2.5 cm diameter) but of a high histological grade, and node positive patients in the sixth decade of life. Furthermore, the oestrogen receptor status and the HER-2 status will also prognosticate for future risk of relapse and therefore, in borderline patients for chemotherapy by other risk factors, these may become the arbiters, as may other prognostic factors (e.g. blood or lymphatic invasion within the tumours specimen remmoved - a lesser prognostic factor than axillary lymph node invasion but nevertheless an adverse prognostic factor.

 

Where the patient is in an unknown risk group and the axillary node situation (i.e. positive versus negative) will determine the treating clinicians view of whether the patient needs chemotherapy, then it is essential that the armpit/axilla is explored by the surgeon to acquire this prognostic information.

 

In the axilla he can do three operations. First he can carry out a ‘full’ axillary dissection where he removes the majority of axillary lymph nodes. This has some good points and some bad ones: the large number of nodes acquired certainly gives the treating physician a good handle on risk category (as the axillary node ‘status’ is the strongest prognostic factor factor for the future in otherwise apparently localised breast cancer). The dissection of this large number of nodes certainly reduces the risk of the breast cancer relapsing in the armpit – a not insignificant risk in the breast cancer population overall, but the price is a complication risk that is mainly that of permanent arm swelling post-operatively. This is usually mild nowadays but can be severe particularly if radiotherapy is given to full dose to the nodes in this region after this operation.

 

Secondly, the surgeon can carry out a sampling of the axilla, where he does not go out to take a majority of the nodes but enough (and six to eight will do) in order to get a prognostic ‘handle’ on the patients risk category for recommending post-operative chemotherapy etc. This operation may be more safely followed by radiotherapy if indicated.

 

Thirdly, the surgeon can carry out what is called a sentinel node biopsy. Here he injects into the breast tumour region a tracer quantity of a radioisotope solution that is taken up into the regional lymphatics. He then maps the most appropriate node to biopsy by a hand held gamma detector probe (which localises the node to which the region preferentially drains) and removes this node. The perceived advantage of this technique is that it disturbs the lymphatic system minimally and yet allows the most prognostically important lymph nodes to be sampled.

 

Sometimes, the patient may fall into the group of patients who will receive full medical/chemo- therapy anyway. Thus, a patient who presents with a five centimetre breast cancer will be advised to undergo post-operative chemotherapy anyway and the need for the surgeon to go into the axilla at all is controversial, as radiotherapy to the axilla will deal with the local control problem here later and if needed.

 

If the above seemed tricky to follow, then the situation is made more difficult as it may nowadays be recommended that the patient does not proceed directly to surgery but has initial chemotherapy. The way that this recommendation has arisen is as follows: When there is a large tumour, it is known that chemotherapy given after the surgery has a good impact on the subsequent relapse risk and it is desirable to get on with this therapy to kill the tumour when the tumour burden (i.e. the total number of dividing cells) is at their least number – and remember that tumours grow exponentially/logarithmically.

 

Also to be considered is the fact that local control of cancer growth in the breast region itself (what is called local control) is best achieved by surgery and radiotherapy when the tumours are small. These facts prompted the treatment of such larger tumours and those with more aggressive characteristics e.g. involvement of overlying skin or tethering to the underlying pectoralis muscle, by primary chemotherapy. By and large this approach has been successful, and the majority of practitioners will now recommend initial/primary chemotherapy for patients presenting with such larger cancers. The surgical principles outlined above then apply.

 

Whether before or after the surgery, adjuvant chemotherapy has role in all but the best prognostic group of patients under the age of seventy (it is not clear why the advantages seen for chemotherapy in patients up to seventy are hardly perceptible beyond that age). Patients with cancers less than one centimetre diameter in general do not need chemotherapy unless node positive in the axilla and those between 1 and 2 cm are only recommended chemotherapy if other risk factors are against them e.g. vascular invasion of cancer cells within the breast, grade 3 histology, HER-2 positive and/or oestrogen receptor negative.

 

The side effects of chemotherapy are by and large known to the public. They include sickness in the early hours and first few days after the drug administration. Nowadays, the medical profession has a good list of anti-vomiting drugs and it is rare for this to be a severe problem. The second side effect is hair loss, a feature of most of the best drugs against this condition and one that can only somewhat be ameliorated by cooling the scalp prior to the administration of the drugs - the mechanism of action of this being via reducing the ‘first pass’ high blood concentrations of drug to the growing hair follicles). Thirdly, inbetween the chemotherapy cycles, the blood count is lowered and the main risk to the patient is due to a reduction in the white cell count (the cell group that protects the patient from bacteria from entering the circulation); any infective episodes or febrile episodes have to be reported in to the doctor. Lastly, apart from individual drugs side effects, the chemotherapy is likely to damage the ovarian function with the production of an artificial menopause.

 

Some of the gains attributed to chemotherapy in younger/pre-menopausal patients are due to the fact that such chemotherapy is likely to cause premature ovarian failure. This removal of oestrogen stimulus (the best established ‘growth factor’ in breast cancer) is now known to lessen the relapse risks of pre-menopausal women with breast cancer and contributes to the lifesaving effects of adjuvant chemotherapy for this group of women - those with oestrogen receptor positive breast cancer. In women who do not achieve ovarian failure with their chemotherapy and for the many who do not receive chemotherapy (except the lowest risk group and possibly those whose tumours are really oestrogen receptor negative) then an artificially arranged ovarian ablation ( laparoscopically performed removal of the ovaries, radiation therapy to the ovaries, or the delivery blocking drug which knocks out the pituitary stimulating hormone that controls ovarian oestrogen function) is desirable.

 

A drug called tamoxifen is an oestrogen antagonist in the body – that is, it blocks oestrogen receptor sites on oestrogen target tissues, and as we have noted above, many breast cancers retain these receptors on their surfaces. There is no doubt that the delivery of tamoxifen for a five year period after the initial surgery/radiotherapy/chemotherapy for breast cancer is attended by a further lowering of risk and it has been indicated in all post-menopausal women and all premenopausal women whose tumours carry the oestrogen receptor (a test by which we assess the likelihood of a breast cancer responding to anti-hormonal therapy). Whether it can equally substitute for ovarian ablation in pre-menopausal women is still undecided and most would cover both options. The commonest side effect of tamoxifen is menopausal flushing; other side effects are numerous but unusual and rarely severe.

 

In recent years another group of hormonally active agents have become available and have successfully challenged tamoxifen for their anti-cancer' role in preventing and treating those breast cancers that are oestrogen recptor positive (i.e. those cancers that are likely to be hormone sensitive. These are called the aromatase inhibitors (and amongst this group are anastrazole and letrozole). These drugs act only in post-menopausal patients and their mechanism is via preventing adrenal steroids (that are a normal physiological product of the adrenals in all humans) from being converted to oestrogens in the body. These are the only source of oestrogens in the post-menopausal woman and inhibition of their production in the body has been shown not only to be effective therapy for post-menopausal women with advanced breast cancer but recently it has been proven that such drugs are slightly better than tamoxifen in preventing relapse of breast cancer in ealier forms of the disease - when used in the adjuvant setting. Thus, anastrazole and letrozole are now used first line after surgery in post-menopausal women with oestrogen receptor positive breast cancer.

 

Another relatively new drug to be discussed is Trastuzumab/'Herceptin'. We have already discussed above that an adverse prognostic feature of a breast cancer is if its cells express a surface protein called HER-2. This is the protein product of an oncogene (EGFR family) and acts to drive tumour progression. Its over-expression on breast cancer cells causes them to be more aggressive and approximately 20% of all human breast cancers over-express HER-2 in this manner. They represent a more aggressive subgroup of breast cancer. Much research has gone into these HER-2 overexpressing cancers lately. It seems that, in this group in particular, aromatase inhibitors beat tamoxifen if the tumour is oestrogen postive, that anthracycline chemotherapy is more active than in HER-2 non-expressing tumours and, most importantly, the drug trastuzumab/herceptin - a humanised monoclonal antibody aimed at the HER-2 receptors on the cancer cells, will prove toxic to these cells.Indeed, adding trastuzumanb to standard chemotherapy has not only proved to increase the response rates in advanced disease but also to improve the efficacy of adjuvant chemotherapy in earlier stage disease.

 

Of the other new drugs, Bevaciszumab (avastin) is a drug that is analogous to trastuzumab but this time targeting a vascular growth factor and this seems to enhance the efficacy of staandard chemotherapy also.

 

Radiotherapy is a very important tool in the management of breast cancer. Radiotherapy refers to the delivery of x-ray beam therapy to the breast or breast and regional lymph nodes in the axilla and above the clavicles the collar bone – i.e. it is a local therapy, in a way like surgery.

 

It is recommended after breast conservation surgery for invasive breast cancer and after mastectomy for larger or riskier growths; in all these situations it reduces the risk of relapse in the breast region. Where the axillary nodes have been involved and particularly where there is evidence of extension of the cancer outsider the capsules of the nodes in the axilla, radiotherapy to this regional node area reduces the risks of recurrence here (although the previous remarks about arm swelling risks in patients who have undergone axillary node dissection must be remembered in this context). Over the last few decades, there has been ongoing controversy over whether the reduction in risks of relapse in the breast and axilla effected by post-operative radiotherapy added to the survival advantages given by the other therapies outlined above. From relatively recent data, there is now good evidence that in node positive patients, post-operative radiotherapy coupled with chemotherapy (the chemotherapy being usually given before the radiotherapy), adds to the survival advantages of chemotherapy alone in these patients.

 

For patients who present with relatively advanced disease, and who, as mentioned above, frequently have initial chemotherapy, there is a case for pre-operative radiotherapy to the breast following initial shrinkage with the drugs. Such a situation arises where there is a large tumour that is tethered deep to the pectoralis muscle. The chemotherapy may shrink it somewhat but the tethering to the underlying muscle may remain after six cycles or so of chemotherapy. Radiotherapy to the breast at this time may facilitate the surgery and increase the chance of obtaining clear microscopic margins at the subsequent total mastectomy.

 

Plowman Oncology London (e-mail: postmaster@pnplowman.demon.co.uk)

The modern radiation system is with high energy linear accelerators and using conformal technology The long term follow-up of radically radiated patients is not as good as surgery (perhaps 40% cure) but, recently, the use of chemotherapy together with both surgery and radiotherapy has led to improved results all round and may allow conservative therapy to substitute operation in some cases – for one has always got radical cystectomy to fall back on if follow-up cystoscopy shows persisting tumour (but against this argument one may be risking that usually sound first principle of oncology which is to go for first time cure).

 

Many clinical trials are currently in progress. There is no doubt that modern chemotherapy, using drugs such as cis-platinum and gemcitabine can cause a good regression in transitional carcinoma of the bladder and for younger and fitter patients many would now employ it in conjunction with local therapy (surgery or radiotherapy), but frequently in a clinical trial context.

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