Oncology Frontier: Tailoring therapy and precision treatment are keywordsat St. Gallen 2015. Tailoring therapy is not a new concept in the endocrine therapy area. Status of menopause has been used as an index for many years. Are there additional markers to helpoptimize endocrine therapy and can you give us some examples to explain it further?

　　《肿瘤瞭望》：个体化治疗和精准治疗是今年圣加仑会议的关键词。个体化治疗在内分泌治疗领域里并非一个新的概念，是否绝经是多年来一直沿用的一个重要指标，除此以外是否还有其他指标有助于优化内分泌治疗呢？您是否可以举一些例子进一步解释？

　　Dr Osborne: You are right. In the endocrine therapy of breast cancer， it has been precision medicine for forty years since the development of the estrogen receptor. We have known that we have to measure the estrogen receptor for its presence or absence in patients’ tumors. If it was there， we gave endocrine therapy; if it wasn’t， we didn’t. That is the definition of precision medicine. We are now beginning to understand that there are other genes or altered genes that impact whether a tumor is going to respond to therapies that target the estrogen receptor. We can measure those now and take them into account to decide on other therapies that might be better or would overcome resistance to endocrine therapy. So， in the future， with HER2 amplification or a mutation in PI3kinase or overexpression of SRC3 or the phosphorylation of some of these proteins like the estrogen receptor， I think we will be able to pinpoint much more accurately whether the patient should get an endocrine therapy as well as whether there should be another therapy given with it to overcome resistance to the treatment we have been giving. There is a lot to be learned but we are getting there in terms of endocrine therapy and a greater precision based on the genetics of the tumor.

　　Dr Osborne:你是对的。随着雌激素受体的研究进展，精确治疗已在乳腺癌的内分泌治疗领域里应用了40年，我们都知道需要检测患者肿瘤的雌激素受体表达情况，如果雌激素受体是阳性的，那么我们就给予内分泌治疗；如果是阴性的，则不给予内分泌治疗，这即是精确治疗的定义。我们现在逐渐开始明白，还存在着一些基因或者是突变基因，可以影响肿瘤对靶向雌激素受体的治疗的反应。我们现在可以检测这些基因，利用这些基因去解释是否采用其他更好的或者说是可以克服内分泌治疗耐药的其他治疗方案。因此在将来，不管是HER-2扩增、PI3激酶突变还是SRC3过表达、或是类似雌激素受体的这类蛋白的磷酸化，我认为我们都可以更加精确地指出患者是否需要内分泌治疗，以及是否还存在其他可以克服现有治疗耐药的治疗方案。目前仍有许多东西需要研究，我们对内分泌治疗的理解，还得基于对肿瘤遗传学更精确的研究。

　　Oncology Frontier: When talking about the duration of adjuvant endocrine therapy， the ASCO and NCCN guidelines have been updated recently. Do you think the expert panel will reach a consensus on an extended duration of endocrine therapy? What suggestion would you make?

　　《肿瘤瞭望》：对于辅助内分泌治疗的持续时间，ASCO和NCCN指南最近均有更新，您认为对于内分泌治疗时间的延长专家组是否已达成共识？您又有何建议呢？

　　Dr Osborne: That’s a difficult question. There probably won’t be total consensus because it really comes down to the individual patients themselves. You can’t make a guideline that applies to every single circumstance in every single patient. It would be easy to say that prolonged endocrine therapy of ten years with tamoxifen， for instance， provides a benefit. It does. But when you have a patient with a very small tumor and has already been treated with five years of tamoxifen or an aromatase inhibitor， their residual risk of a recurrence is very small， so the benefit of extending adjuvant endocrine therapy for another five years would in my opinion be outweighed by the side effects and cost of the medicine. So it is really difficult to give a general guideline for everyone. However， having said that， it does look like that longer durations of adjuvant endocrine therapy are better and for certain patients I would recommend longer durations.

　　Dr Osborne:这是个难题。目前尚不能达成共识，因为归根结底这还是取决于患者自己。你不能将一个指南适用于任何患者任何情况。举个例子来说，我们很容易都知道延长他莫昔芬的内分泌治疗至10年可以获益，确实如此，但当你有一个患者，其肿瘤非常小，并且已经接受5年的他莫昔芬或者芳香化酶抑制剂的治疗，其残留的复发风险非常小，因此再延长5年的辅助内分泌治疗的益处，在我看来是小于药物的副反应及药物的成本的。所以，真的很难为所有人提供一个通用指南。然而不得不说，辅助内分泌治疗的时间更长确实更好，对于某些特定的患者，我推荐更长时间的内分泌治疗。

　　Oncology Frontier: What’s your view onthe necessity for combining ovarian function suppression with tamoxifen or aromatase inhibitors? How can we identify the patients indicated for such therapy?

　　《肿瘤瞭望》：对于抑制卵巢功能联合他莫昔芬或芳香化酶抑制剂的必要性，您是怎么看的？我们如何区分出需要此类治疗的患者呢？

　　Dr Osborne: Right now， we should use the eligibility criteria for the setting. If there is a young patient who has had chemotherapy and preserved ovarian function after chemotherapy and had a high risk tumor (which would be why they received chemotherapy in the first place)， then that patient would deserve to have ovarian suppression with an aromatase inhibitor or tamoxifen. The problems we get into there are side effects and these side effects， particularly in a young woman， can be substantial (50% incidence of clinical depression for instance). It is going to be a balance. For those patients who can’t tolerate it， we would have to fall back on the standby of tamoxifen， which is better tolerated from this point of view and the side effects can be more easily treated. But for a high-risk patient who preserves menstrual function after chemotherapy， that would be the patient to consider ovarian suppression and an aromatase inhibitor or tamoxifen.

　　Dr Osborne:现在我们应该使用标准的治疗原则。如果有一个接受过化疗的年轻患者，在化疗之后还保有卵巢功能，但却有高危因素（这也是为何首选化疗的原因），那么这个患者就应当接受卵巢功能抑制联合芳香化酶抑制剂或他莫昔芬治疗。我们所面对的主要问题就是联合治疗的副反应，这些副反应，特别是在年轻女性中，是非常巨大的（例如50%的临床抑郁症的发生率）。这需要达到一个平衡。对于那些不能忍受副反应的患者，我们则需回到最初的他莫昔芬治疗上，从这点上看其副反应更易耐受，也更易治疗。但对于具有高危因素的在化疗后还保留正常月经功能的患者，则需考虑抑制卵巢功能抑制剂和芳香化酶抑制剂或三苯氧胺治疗。

　　Oncology Frontier: We know for many years that ER-positive is a marker indicated in endocrine therapy. Other biomarkers， like Ki-67 and progesterone receptor (PgR) can help to identify the patient response to chemotherapy. However， the role of ER has many aspects as your have mentioned in your presentation here. Could you elaborate a little on this?

　　《肿瘤瞭望》：我们都知道一直以来ER阳性是内分泌治疗的一个标志性指征。其他的生物标记物，如Ki-67和孕激素受体（PgR）可以帮助确定患者对化疗的反应性。然而，就像您在演讲中提到的那样，ER的作用是多方面的，您能就此详细解释一下吗？

　　Dr Osborne: Progesterone receptor has been a difficult one， partly because it is more difficult to measure and partly because its expression is influenced by the biology of the tumor and what is going on in the tumor， but also by the estrogen level in the patient. To control for all of these things is difficult and probably why measurement of progesterone receptor has been problematic in terms of whether it predicts if a patient is going to respond to endocrine therapy or not. So overall， it turns out that it is not a very good marker for that. We are left with the estrogen receptor. It turns out that there are mutations in the estrogen receptor that we didn’t think were there years ago. They are present in patients who have resistant disease to standard endocrine therapies and now we can measure for those mutations and if they are present， then that patient is going to be relatively resistant to endocrine therapy. Hopefully in the future， we will have better treatments to block those mutant receptors， but right now we don’t. That may trigger the physicians to give chemotherapy instead of endocrine therapy when there is an ER mutation present.

　　Dr Osborne:孕激素受体一直以来都是一个复杂的标志物，部分原因是因为其难以检测，部分是因为其表达受肿瘤的生物学特性及肿瘤的状态所影响，同时还受患者雌激素水平的影响。要想控制好这些事情是非常困难的，或许这也是为什么孕激素受体作为预测患者是否对内分泌治疗有反应的指标成问题的原因。所以总的来说，孕激素受体不是一个很好的标记物。剩下来的就是雌激素受体。现在证实，雌激素受体可发生突变，这和过去我们的认知不符。这些突变存在于那些对标准内分泌治疗抵抗的患者中，因此现在我们可以对这些突变进行检测，如果存在突变，这些相应患者就会对内分泌治疗抵抗。希望在将来，我们将有更好的针对这些突变受体的治疗方法，但目前为止我们还没有。这就会使得肿瘤内科医生在ER突变发生时用化疗来替代内分泌治疗。

　　Oncology Frontier: Where are we now in the treatment of ER-positive breast cancer?

　　《肿瘤瞭望》：目前对于ER阳性的乳腺癌治疗进展如何？

　　Dr Osborne: We do a very good job with it. Drugs like tamoxifen particularly， and the aromatase inhibitors， have contributed to reductions in mortality from breast cancer overall since 1990 when tamoxifen became widely used in breast cancer. It is the best treatment we have for ER-positive breast cancer which is the most common form of the disease. Is there room for improvement? Yes， and that is where giving longer durations of endocrine therapy may be useful in some patients， by combining it with other drugs to circumvent the resistance mechanisms like growth factor receptor signaling， and by measuring mutations and then coming up with other drugs that block that mutated receptor better. There is still a long way to go， but our treatment for endocrine-responsive breast cancer is really quite good today.

　　Dr Osborne:我们对此作了大量的工作。药物，特别是他莫昔芬，以及芳香化酶抑制剂，自1990年以来他莫昔芬广泛用于乳腺癌的治疗后，显著降低了乳腺癌的总体死亡率。这是对最常见的乳腺癌类型——ER阳性乳腺癌最有效的治疗方案。那是否还有改进的余地呢？答案是肯定的，那就在于延长内分泌治疗的时间在一些患者中是有效的，通过联合其他药物避免耐药机制例如生长因子受体信号通路，通过检测突变，然后想出其他更好的阻断突变受体的药物。未来我们仍有很长的路要走，但目前对于激素敏感的乳腺癌的治疗还是很好的。