Breast cancer: Dangerous genes

Nadia Harbeck is constantly on the move: first from Barcelona to Munich, then from the airport to the clinic, now from her office to a patient. "I'll be right back," she assures us, hurrying across the corridor of the LMU Women's Clinic. She only returned from the European Cancer Congress a few hours ago, her black trolley case is still in the corner of her office with a rain jacket and a bag from the bakery on top. The paraphernalia of a traveler. It's hardly worth unpacking, "in a few days I'm off to a conference in China," the professor explains succinctly as she settles into her office chair fifteen minutes later. Crazy day? She laughs, her blonde curls bouncing. "No, actually quite normal."

Then it's time for the next leap, this time only mentally, back into the past. More precisely: to May 14, 2013, the day on which actress Angelina Jolie published an open letter in the New York Times entitled "My medical choice".

Jolie was never Nadia Harbeck's patient, but she was still very present in her consultation room for a long time: in the minds of worried women who had read about her fate. “We were literally overrun after the article - the phone never stopped ringing and consultation appointments were booked up months in advance,” recalls the head of the Breast Center and the Oncology Day Clinic at LMU Hospital. The actress had made her BRCA mutation and the precautionary removal of her breasts public. Doctors call this procedure a bilateral prophylactic mastectomy. And many women around the world wanted to know: Is there cancer in my genes? How high is my personal risk? How can I protect myself?

Most common type of cancer in women

Every year, more than two million people worldwide are diagnosed with breast cancer, 70,000 of them in Germany alone. This makes breast cancer the most common type of cancer in women. In most cases, it occurs spontaneously, so genes play no role. “In five to ten percent of cases, however, a mutation in the genetic material increases the risk by up to 80 percent,” explains Harbeck. A fact that was little known for a long time. This changed abruptly with Angelina Jolie's article - and with such lasting effect that experts even speak of a “Jolie effect”: Since then, many women and men have seized the opportunity to take precautions and clarified their risk with the help of specialists.

“It's good that the case has made so many people aware of hereditary breast cancer,” says Harbeck. At the same time, she is glad that the situation has calmed down over the years, as there was a lot of uncertainty. However: “Not all women with a family history of cancer have this genetic mutation. And even if a mutation is present, there are many other ways of dealing with it besides a mastectomy.”

BRCA1, BRCA2, PALB2, CHEK2, RAD51C, ATM, BRIP1, CDH1, TP53: Research has now identified a whole series of genes whose mutations can increase the risk of hereditary breast cancer. It is estimated that around half of the disease-causing gene mutations are now known and others are currently being investigated in more detail. The excitement has died down, but the attention has remained: Many people are taking a closer look at their family history and asking questions. What caused the aunt to die so young? What type of cancer did grandma have? Are there a conspicuous number of cancer cases in my family?

Clarity through genetic testing

The family history provides crucial information about cancer genes. In addition to a frequent occurrence of the disease, an early age of onset, bilateral occurrence and breast cancer in a man are also important pieces of information. 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 have their risk checked at special human genetic counseling centers,” explains Harbeck, who is both a gynecologist and an oncologist. If the suspicion is confirmed during the consultation, a genetic test can provide clarity. A few drops of blood are enough for this.
Every woman deals with the issue differently, says Harbeck. Some want certainty from the test, others don't under any circumstances. Some decide to take drastic steps and have their breasts and ovaries removed as a precaution. Others wait for the onset of the disease or find security in close preventive care. “However, it often makes sense to remove the ovaries in particular once family planning has been completed, because preventive care is less possible there than with breast tissue,” explains Harbeck, talking a little about her patients. “I have one patient, for example, who is proactive in raising awareness within her family and talks openly about her genetic mutation.” In general, she observes that many women today are well informed, educated and relaxed about the topic. “Most of them know that we have a lot to offer them and can provide them with good support.”
Prevention and early detection play a crucial role in this. In the case of a genetic burden, it starts earlier, takes place at shorter intervals and with more examination methods. Regular MRI scans, for example, are then standard.

But prevention is also a decisive factor beyond genes. “The earlier we detect a tumor, the better the chances of recovery,” says Harbeck. The fact that breast cancer is considered highly treatable today and can be cured in around 80 percent of cases is also thanks to her. For many years, she has not only been treating patients, but also researching how therapies can be improved and carried out more gently. For example, with the West German Study Group (WSG), in whose studies on avoiding chemotherapy more than 15,000 women suffering from breast cancer have already taken part. It has repeatedly contributed important findings and thus driven research forward.

New antibody agent

For example, the results of an international study under her co-leadership have just been published. The researchers tested a drug for a specific form of breast cancer that is often associated with tumors in the brain. These are very difficult to treat because most drugs are unable to cross the blood-brain barrier. However, a targeted antibody-drug conjugate can do just that - and thus significantly increase the chances of survival. 90 percent of all patients were still alive one year after starting treatment. “These results are fantastic and a great hope for patients with brain metastases,” says Harbeck.

Today, she is an internationally sought-after expert, helps shape the guidelines for treating the disease, has presented her research findings at congresses worldwide and has received numerous awards for her work, most recently - together with her colleague from the WSG, Professor Nitz - the German Cancer Prize 2023 and also the only German scientist to date to receive the ESMO Lifetime Achievement Award 2020 from the European Cancer Society. Improving cancer therapy is her life's work. “I am interested in two things: firstly, how to make the therapies themselves even more effective. And secondly, how to use them as gently as possible.”

Effectiveness is one thing, tolerability is another. “We take a very close look at which therapies are really necessary - and what can be dispensed with without reducing the chances of recovery.” For example: Is stressful chemotherapy really necessary? To decide this, the tumor is analyzed in detail and tested to see how well it responds to anti-hormone therapy, for example. Is it possible to prove that the tumor forms fewer new cells as a result? “We set ourselves interim targets and keep checking: What is working well? How does the tumor react to what?” Especially in the early stages and when only a few lymph nodes are affected, chemotherapy can often be avoided.

Individualized therapy

The keyword for modern and gentle therapies is individualization. “Nowadays, we no longer do run-of-the-mill therapies, but tailor everything precisely to the woman affected.” The components available for treatment, such as chemotherapy, radiotherapy and surgery, as well as immunotherapies, anti-hormone therapies and antibody therapies, must be combined appropriately. There are many factors to consider: In which order are the therapies used? What is the best way to combine them? What dose is needed? Which active ingredients are particularly promising?

“A lot has happened in cancer therapy in recent years and the potential is far from exhausted,” says Harbeck. Immunotherapies, for example: “Just as children sometimes hide under the comforter, tumors hide from the immune system - and with modern drugs you can simply pull the blanket off them,” explains the doctor. This is just one of many milestones in cancer therapy.

To date, three antibody drugs have been approved for the treatment of breast cancer in Germany. Harbeck wants to help ensure that there are many more; she believes that the potential of such therapies is far from exhausted. A large, globally unique study for patients with early, non-metastatic, HER2-positive breast cancer has been running in Germany for around a year on the initiative of the WSG. They are injected four times with an antibody drug before their operation, which makes the therapy much easier and shorter for the women.

Do you have to be treated at a leading university hospital to benefit from these modern therapies? Harbeck shakes his head. “We have 255 certified breast cancer centers in Germany, where women can rely on modern treatment in line with guidelines.” She is also fighting to make her care more effective - and more comfortable for patients.
Harbeck is not only a renowned researcher, but also a mother of four. She knows the needs of women and how they are caught between work and family. “You can take a lot of the pressure off,” she says. This is also part of her work and the large healthcare research studies at her clinic. For example, her team at the LMU Clinic was able to show that digital applications such as apps and artificial intelligence can provide good therapy support for women. “They can be used, for example, to control whether they really need to go to the clinic or doctor for appointments all the time or whether this is enough as needed.”

Nadia Harbeck originally became a gynecologist because she wanted to be there for women at all stages of life and also wanted to work with healthy people. This changed somewhat when she branched out into oncology. “But making people healthy is also a very good job,” she says, taking a sip of coffee and squinting at her watch. She's on the move again and has to get going. Her patients are waiting.

Prof. Dr. med Nadia Harbeck, Professor of Conservative Oncology at LMU since 2011, is a specialist in gynaecology and obstetrics and heads the Breast Centre, the Oncology Day Clinic and the Center for Familial Breast and Ovarian Cancer at LMU's Women's Hospital.