Breast cancer: dangerous genes

Nadia Harbeck is constantly on the go: first from Barcelona to Munich, then from the airport to the hospital, now from her office to a patient. “I’ll be right back,” she promises and dashes down the corridor of LMU’s Clinic and Polyclinic for Obstetrics and Gynecology. Just a few hours ago she returned from the European Cancer Congress, and her black trolley case is in the corner of her office. On top of the case is a rain jacket and a bag from the bakery – the paraphernalia of a traveler. It is hardly worth unpacking, as “in a few days, I’m off to China for a conference,” explains the professor briskly as she sits down in her office chair 15 minutes later. A crazy day? She laughs, and her blonde locks bob up and down. “No, actually it's a normal day for me.”

Then it’s time to get going again, albeit not physically this time, but mentally back to the past. More specifically, back to 14 May 2013, the day on which the actor Angelina Jolie published an open letter in the New York Times with the title: “My medical choice.”

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Although Jolie was never Harbeck’s patient, she has been a presence in her consulting room all the same: in the minds of worried women who had read about her fate. “After the article came out, we were swamped – the phone was hopping all day long, consultation appointments were booked out months in advance,” recalls the head of the Breast Center and the Oncological Day Clinic at LMU University Hospital.

In her article, the actor described her BRCA mutation and the precautionary removal of her breasts. Doctors call this procedure a bilateral prophylactic mastectomy. And then many women around the world wanted to know: Is cancer lurking in my genes too? How high is my personal risk? How can I protect myself?

Most common type of cancer in women

Over two million people worldwide develop breast cancer every year – 70,000 in Germany alone. This makes breast cancer the most common cancer in women. In most cases, it arises spontaneously, meaning genes are not a factor. “In five to ten percent of cases, however, a genetic mutation drives up the risk by up to 80 percent,” explains Harbeck. For a long time, few people were aware of this.

This changed overnight with Angelina Jolie’s article – and in such a lasting manner that experts speak of a “Jolie effect.” Many women and men have since sought out an appointment and had their risk assessed by a specialist. “It’s good that the case made so many people aware of hereditary breast cancer,” says Harbeck. At the same time, she is glad the situation has calmed down again over the years, as people were very rattled by it. Moreover: “By no means all women with cases of cancer in their family have this genetic mutation. And even if a mutation is present, there are many other options for dealing with the situation besides a mastectomy.”

BRCA1, BRCA2, PALB2, CHEK2, RAD51C, ATM, BRIP1, CDH1, TP53: Researchers have identified a whole range of genes whose mutations can increase the risk of hereditary breast cancer. It is estimated that around half of pathogenic genetic mutations are known today, and others are being investigated in more detail.

While the excitement around the issue has died down, it has remained lodged in people’s minds. Many people are taking a closer look at their family history and asking questions: My auntie who died young – what disease did she have? What kind of cancer did grandma have? Is there an unusually high number of cancer cases in my family?

Certainty through gene test

Family history provides vital clues to the presence of cancer genes. In addition to frequent occurrence of the disease, other indications include people developing the disease at a young age, having cancer in both breasts, and cases of breast cancer in male family members. Angelina Jolie’s mother, for example, died of breast and ovarian cancer at the age of 56, and she also lost her grandmother and an aunt to the disease.

“Anyone who suspects they may be affected can get their risk assessed at special human genetic clinics,” explains Harbeck, who is both a gynecologist and an oncologist. Should the consultation substantiate the initial suspicion, a gene test can provide certainty – a few drops of blood are all that are needed.

Every women deals with the issue differently, observes Harbeck. Some take the test because they want to know for sure; others don’t want to know. Some take drastic measures and opt to have their breasts and ovaries removed as a precaution. Others wait for the onset of the disease or find reassurance in continuous monitoring. “In the case of ovaries in particular, it can often make sense for women to have them removed once their family planning is complete, because prevention is trickier for ovaries than it is with breast tissue,” explains Harbeck. “I’ve got a patient, for example, who goes on the offensive in her family and speaks openly about her gene mutation.” In general, Harbeck finds that many women today deal with the topic in a calm, well-informed manner. “Most of them know we can offer them a lot in terms of treatment options and guidance.”

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Prevention and early detection play a decisive role. For people with a genetic predisposition, this process begins earlier, takes place at shorter intervals, and involves a wider range of examination and testing methods. Regular MRI scans, for instance, are standard in such cases.

But even leaving genetics to one side, prevention is a crucial factor. “The earlier we detect a tumor, the better the chances of recovery,” says Harbeck. The fact that breast cancer today is considered a very treatable disease and can be cured in around 80 percent of cases is owing to the efforts of doctors like her. For many years, she has not only been treating patients, but also researching how to improve therapies and make them gentler on patients. This includes her work with the West German Study Group (WSG). More than 15,000 women with breast cancer have already taken part in the WSG’s studies on avoiding chemotherapy. Harbeck has repeatedly contributed important insights and driven advances in research.

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New antibody-drug conjugate

She recently co-headed an international study, for example, whose results have just been published. The researchers tested a drug for a certain type of breast cancer which is often associated with tumors in the brain. These tumors are very difficult to treat, because most active agents cannot overcome the blood-brain barrier.

A targeted antibody-drug conjugate, however, can do precisely that – and thus significantly increase the chances of survival. 90 percent of all patients were still alive one year after the start of treatment. “These results are fantastic and offer great hope to patients with brain metastases,” says Harbeck.

Today, she is a much sought-after expert internationally and helps shape the guidelines for treating the disease. She has presented her research findings at congresses around the world and has been awarded numerous prizes for her work, recent examples including the 2023 German Cancer Award together with her colleague at the WSG, Prof. Ulrike Nitz, and the ESMO Lifetime Achievement Award 2020 by the European Society for Medical Oncology, making her the only German scientist to date to have received this accolade. Improving cancer therapy is her life’s mission. “I’m interested in two things here: One is how to make the therapies themselves even more effective, and the other is making therapies as gentle as possible on patients.”

Harbeck continues: “We look very closely to see what therapies are really necessary – and which we can omit without reducing the chances of recovery.” For example: Does the patient really need to undergo a heavy course of chemotherapy? To decide this, the tumor is precisely analyzed and tested – to see, for example, how well it responds to antihormone therapy.

Is it possible to determine that the tumor is forming fewer new cells as a result of such treatment? “We set ourselves intermediate goals and repeatedly check: What’s having a positive effect? How is the tumor responding to this or that treatment?” In this way, chemotherapy can often be avoided, especially in early stages and when few lymph nodes are affected.

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Individualized therapy

The keyword for modern therapies that are gentle on patients is individualization. “We don’t do off-the-shelf therapies anymore, but tailor everything precisely to the patient.” To this end, the available treatment options – things like chemotherapy, radiotherapy, and surgery, but also immunotherapies, antihormone therapies, and antibody therapies – have to be suitably combined.

There are a lot of factors to consider here: In which order should the therapies be deployed? What is the most effective way of combining them? What doses are needed? Which drugs are most promising? “Over the past few years, there has been a lot of progress in cancer therapy, and the potential is still far from exhausted,” says Harbeck. She cites the example of immunotherapies: “Like children hiding under the bedcovers, so tumors hide from the immune system – and modern drugs pull off the covers.” Moreover, this is just one of many milestones in cancer therapy, she adds.

Three antibody drugs for the treatment of breast cancer have been approved in Germany to date. Harbeck wants to help ensure that many more join them. She thinks a lot of potential still remains to be exploited in such therapies. For the past year or so, a large study has been underway in Germany, looking at patients with early, non-metastasized HER2-positive breast cancer. Unique worldwide, the study was created on the initiative of the West German Study Group. Before undergoing surgery, the patients are given four separate injections of an antibody drug, which significantly alleviates and shortens the therapy for the women.

Do you have to be treated at a leading university hospital to avail of these modern therapies? Harbeck shakes her head. “We have 255 certified breast cancer centers in Germany, where women can be assured of getting modern treatment in accordance with the latest guidelines.” She also fights to make the care women receive more effective – and more comfortable.

Harbeck is not only a well-known researcher, but a mother of four. She knows the struggles of women, the pressures of work and family life. “There are various ways of easing the burden on women,” she says. This too is part of her work and part of the large research studies into medical care conducted at her clinic. Her team at LMU University Hospital demonstrated, for example, that digital tools such as apps and artificial intelligence can provide useful support for women with their treatment. “You can use these applications to determine, for example, whether patients really have to come to the hospital or visit their doctor all the time, or whether these visits can happen on an as-needed basis.”

Nadia Harbeck originally became a gynecologist because she wanted to support women in all phases of life and also wanted to work with healthy people. When her career branched into oncology, this changed somewhat. “But making people healthy is very rewarding too,” she says as she takes a sip of coffee and squints at the clock. And then she is off again – her patients await.

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Prof. Dr. med. Nadia Harbeck, has been Professor of Conservative Oncology at LMU since 2011. A specialist in obstetrics and gynecology, she heads the Breast Center, the Oncological Day Clinic, and the Center for Familial Breast and Ovarian Cancer at LMU’s Clinic and Polyclinic for Obstetrics and Gynecology.

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