“Every lump in a young woman should be investigated”

<p class="article-intro">During the European Society of Medical Oncology (ESMO) Breast Cancer 2019 meeting, breast cancer expert Prof. Dr. med. Olivia Pagani from the Oncology Institute of Southern Switzerland (IOSI) gave two talks about the rarely occurring breast cancer in women younger than the age of forty. We got the chance to talk to her personally about the major challenges in diagnosing and treating these patients compared to older ones, and how she thinks fertility issues should be addressed.</p> <hr /> <p class="article-content"><p><strong>Did you enjoy the ESMO Breast Cancer 2019 meeting?</strong><br /> <strong>O. Pagani:</strong> Of course, there really have been a lot of interesting talks from many renowned breast experts. However, what I did not like was that there were a lot of parallel sessions, which always makes you need to choose. Sometimes during a session, I regretted that I did not attend another. It was a little bit like at the American Society of Clinical Oncology (ASCO) annual meeting: you have to jump from one room to another, which I think is not ideal. Certainly, I do understand that otherwise the congress would be much longer. Additionally, there are already so many breast cancer congresses, which makes it difficult to really learn something new. In general, I think it is a little bit too much.</p> <p><strong>You are doing a lot of research on breast cancer in young women. In this regard, &ldquo;young&rdquo; women are defined those aged &le; 40 at diagnosis. Why is there a need to cluster them in a separate group?</strong><br /> <strong>O. Pagani:</strong> The age limit of forty to define young women is arbitrary, but was decided when it was realized that these women younger than forty years are a specific subgroup of premenopausal women, considering e. g. fertility issues, which are less common in women older than forty, even if they are premenopausal. Thus, therapeutic side effects are even more relevant.<br /> In case of iatrogenic menopause, side effects are often worse in younger individuals, as they are still far from approaching their natural menopause. This also has an impact from a psychological point of view. Additionally, cancer biology is distinct. We do not exactly know how it is different, but we see the younger the women are, the higher is their probability of having an aggressive disease. This is why young women with breast cancer need to participate in specific clinical trials, and should have specific support, treatments and consideration.</p> <p><strong>Is it known why younger women tend to have more aggressive tumours of the breast?</strong><br /> <strong>O. Pagani:</strong> In general, younger women are more likely to have a human epidermal growth factor receptor 2 (HER2+) positive and triple-negative histology, with a shift from the luminal A-like to luminal-B like disease. However, with the same histology and stage, the prognosis is exactly the same, whether the patients are forty or eighty. Most clinicians have the misconception that young women have a worse prognosis, just because they are young, and tend to overtreat them with chemotherapy, surgery and radiation therapy. But, if their tumour subtype is the same, all women should be treated equally.<br /> Apart from that, the specific problem are the luminal A subtype patients: it has been shown that in young women with luminal A subtype, prognosis actually is worse than in older women. It is not clear why, but one possibility could be that adherence to endocrine therapy is much worse in young women, probably because of the side effects. Still, studies are ongoing to check if there are some genomic or proteomic issues involved, e. g. a higher number of <em>phosphoinositide 3-kinase</em> (PI3K) or GATA <em>binding protein 3</em> (GATA3) mutations. Possibly, this could explain the bad prognosis related to age. However, it remains a controversial issue which we still do not understand fully.</p> <p><strong>How frequently does breast cancer in young women occur?</strong><br /> <strong>O. Pagani:</strong> Altogether, it can be said that breast cancer in young women is a rare disease. The frequency differs between countries: in the Western world, breast cancer before forty makes up for approximately 5 % of the total breast cancer cases. In developing countries, it is twice as high, namely around 10 % , but there are also more young women than in Western countries which leads to a different age distribution.</p> <p><strong>Which are the challenges in diagnosing breast cancer in young women?</strong><br /> <strong>O. Pagani:</strong> In young women, there is a big problem concerning diagnosis: it happens very often that women feel a lump in their breast and then visit the gynaecologist. But if the gynaecologist is not really aware of breast cancer in young women, they quite often do not think that a lump in a woman at such a young age might actually be breast cancer. This tendentially leads to a late diagnosis when the women are already symptomatic. Additionally, mammographic breast screening is difficult in young women, as they have denser breasts. Some countries are already adapting the starting age of mammographic screening, from fifty to forty-five, especially in Northern countries, where they are starting to screen women from the age of forty-five. Unfortunately, the data are not yet available.<br /> In women with higher risks, however, like a significant family history, a germline mutation in a cancer predisposition gene like BRCA, or those who have other risk factors (like chest radiation therapy in childhood/adolescence), the screening process has to be adapted, and should already start much earlier, depending on the individual situation. The best tool then is breast magnetic resonance imaging (MRI) associated with breast ultrasound.</p> <p><strong>Is the standard of care different in young women with breast cancer compared to older ones?</strong><br /> <strong>O. Pagani:</strong> There are significant differences in treatment only concerning endocrine therapy, as young women often undergo ovarian function suppression, especially intermediate and highrisk patients. Usually it is done with gonadotropin-releasing hormone (GnRH) agonists, because their effects are reversible, unlike with oophorectomy. But as they are expensive, it is also a matter of availability, especially in low income countries. In rich countries like the Western ones, GnRH modulators are the best way to suppress the ovaries, even if they have significant side effects related to premature menopause. These include hot flashes, which can be dealt with e. g. acupuncture, vaginal dryness, which can be addressed with some topic drugs or laser treatment that has become available the last years, sleep problems, myalgia, and so on. If the patients are only thirty-five years of age when these symptoms begin, it is psychologically even more difficult, and additionally can influence the libido and thus the sexual relationship of a couple. To address all these very complex side effects, a dedicated and interdisciplinary team is needed.<br /> Oophorectomy is much less expensive, but of course it is a pity to do it in young women as it is irreversible. It has a high impact on quality of life. However, there is no difference in survival rate compared to treatment with GnRH agonists, and the side-effects are more or less the same.<br /> It is also very important to note that aromatase inhibitors are contra-indicated in premenopausal women. They can only be applied together with ovarian suppression, because they stimulate the pituitary gland and the ovaries to produce hormones. Aromatase inhibitors decrease the level of oestrogen in the blood, so if the ovaries are not suppressed, the activated pituitary gland stimulates the ovaries. Thus, if aromatase inhibitors are applied, additionally the ovaries need to be suppressed.<br /> Apart from that, concerning chemotherapy and targeted therapy, the indications and schedules are the same in young and elderly women with breast cancer. Of course, in clinical trials regarding breast cancer, the proportion of young women is low, because they are rare. Thus, the data are not as robust as they are in menopausal women. Still, when all the trials in chemotherapy and targeted therapy have been analysed with regard to the subgroup of young women, it was found that the therapeutic effect of chemotherapy and targeted therapy was the same. Therefore, treatment indications are the same, apart from endocrine therapy.</p> <p><strong>Should young women diagnosed with breast cancer rather receive mastectomy instead of breast-conserving surgery?</strong><br /> <strong>O. Pagani:</strong> A meta-analysis of more than 20 000 cases of breast cancer in young women has recently shown that there is no difference in survival between patients undergoing mastectomy and those undergoing breast-conserving surgery. Of course, breast conserving surgery is associated with a slightly increased local relapse &ndash; we know that. But young women should not be treated differently from older women. The indications for breast-conserving surgery or mastectomy are the same as in older women, unless the patients show a mutation.</p> <p><strong>How is the fertility issue in young women with breast cancer addressed? Very often, they do not have children yet.</strong><br /> <strong>O. Pagani:</strong> As I have mentioned, a multidisciplinary team is needed to treat young women with breast cancer, including a fertility expert. Fertility should be discussed before starting any treatment. GnRH agonists during chemotherapy can sustain fertility, but there are also other measures. Very often, oocyte cryopreservation is used. If the woman is in a stable relationship, embryo cryopreservation may be used, in some cases ovarian tissue cryopreservation, too. It is discussed individually according to the patient&rsquo;s situation. The major problem with these fertility preservation techniques is that they are very expensive. In Switzerland, the financial situation is rather good, and they are reimbursed only since the beginning of this year. In many other countries, this is not the case, which remains quite a problem.</p> <p><strong>Do you think there is a progress in treating young women with breast cancer? What are the future challenges?</strong><br /> <strong>O. Pagani:</strong> I think ovarian function suppression has made a change, as it has brought a clear outcome benefit. Young women with breast cancer in general are living longer than before. We still have some work to do in educating doctors, e. g. gynaecologists and also those who are not breast cancer experts, not to overtreat the patients just because they are young, and sensitize them to the topic. They need to know that breast cancer in young women is there, and that every lump in a young woman should be investigated. Even more dramatic is breast cancer in young women during pregnancy, as it is very difficult to be diagnosed, and late diagnoses are very common. Thus, a very comprehensive and multidisciplinary team is obligatory.</p></p>