Delays in Surgery

The backlog in surgery has been covered widely in the media and, although efforts are now being made to catch up, delays for some patients are unfortunately going to continue for some time. These may still occur for simple breast conserving surgery (sometimes referred to as wide local excision or lumpectomy), but the bigger problem is with delays for women needing reconstructive surgery after mastectomy since this takes up a lot more operating theatre time and resource.

One approach to dealing with this is with pre-operative (sometimes called neoadjuvant), endocrine therapy with drugs like tamoxifen or aromatase inhibitors (usually letrozole or anastrozole).  Around 75% of breast cancers have protein receptors called Oestrogen Receptors and are referred to as ER+ve (not OR+ve because the Americans call it Estrogen and they carry more clout than us). Most of these ER+ve breast cancers are sensitive to the hormone oestrogen which stimulates their growth. Endocrine therapy works either by blocking the effect of oestrogen on the cancer cell (tamoxifen) or stops the production of oestrogen (aromatase inhibitors).

Normally endocrine therapy is given after surgery for 5 years or more to women with ER+ve breast cancers (so called adjuvant therapy).This can be enormously effective treatment and saves many hundreds of thousands of lives.

But for some (not all) ER+ve breast cancersendocrine therapy before surgery can control and shrink the primary tumour for many months. This gives the opportunity to delay surgery for a few months at least, without jeopardising the outcome.

The question is choosing which ER+ve breast cancers are suitable for this approach; it doesn’t work for all of them. My colleague, Professor Mitch Dowsett, who works with me at the Royal Marsden Hospital and Institute for Cancer Research in London, has led a team of international experts to come up with guidelines addressing this question. We established three groups of patients with ER+ve breast cancer.

Group 1 have high levels of ER in their breast cancers and also high levels of another marker: PgR (which stands for progesterone receptor). Patients with this type of cancer will do very well on preoperative endocrine therapy for several months while waiting for surgery. 

Group 2 have relatively low levels of ER and PgR. Their cancers are unlikely to be controlled with endocrine therapy, and they need to be prioritised for early surgery. Some of this group may benefit, however, from preoperative chemotherapy which, again, buys several months before surgery is required.

Group 3 involves patients with intermediate levels of ER and PgR in their cancers. The best approach for this group is to have a trial of endocrine therapy for around two weeks followed by another biopsy to check whether the tumour has stopped proliferating (using a test called Ki67). 

If so, then preoperative therapy can continue as for Group 1; if not, then surgery needs to be prioritised.

So, if you are faced with a possible delay in surgery it’s worth discussing with your team whether this approach of preoperative endocrine therapy might be appropriate for you

Genomic testing: Oncotype DX etc.

In recent years, genomic testing has become available for selected patients with ER+ve cancers. These include Oncotype DX, Endopredict, and Prosigna. They are all based on studying the activity of selected genes within the cancer: Are they highly active or are they switched off? From this information, the likelihood or probability of the cancer recurring over the next 10 years or so can be calculated, and this is very helpful in deciding whether a patient would benefit from chemotherapy, in addition to endocrine therapy, or not. This decision is also based on other factors, including: the size of the cancer, the grade (determined by looking at cancer cells under the microscope) and whether the nodes are involved or not. But these give only an approximate guide and the genomic score can often give a more accurate prediction.

However, there is a snag when preoperative endocrine therapy is used. The treatment itself can modify the activity of the cancer genes being measured.  For example, genes involved in tumour proliferation can be switched off. This approach can therefore lead to a false result at the time of surgery. One solution is to do the genomic test on the core needle biopsy at the time of diagnosis, before any treatment has been started. Most breast cancer specialists feel this is a very reasonable approach, but, strictly speaking, it has not been formally tested in large numbers of patients and the NHS can therefore be reluctant about funding. More confirmatory work in this area is urgently needed.

Oestrogen and Covid 19

And finally, someone has written to me with the information that oestrogen may be a protective factor in reducing the severity of Covid-19 infection, and therefore worrying about the use of the aromatase inhibitors letrozole and anastrozole. I haven’t seen this data, but I’m sceptical. I’m wondering if they’re based on the higher incidence of severe Covid-19complications and death in men than in women. If so, then this is a weak argument, since, in middle age and beyond, oestrogen levels are as high in men as in women. In contrast, the benefits of letrozole and anastrozole are well established and very significant. So, keep taking your tablets! And as always, suggestions for future blogs are most welcome.

Ian E Smith

Professor of Cancer Medicine

Royal Marsden Hospital and Institute of Cancer Research, London