We had the opportunity to speak with Assist. Prof. Dejan Juric, a Croatian-American clinical investigator, Harvard professor of oncology, and medical oncology specialist at Massachusetts General Hospital, to discuss current developments and future directions in early breast cancer care.
The key is partnership with the patient
Early breast cancer research is undergoing a transformative shift, fueled by a deeper understanding of tumor biology and the rapid progress of precision oncology. Professor Juric, a leading clinical investigator in the development of targeted therapies, recently visited Slovenia for a talk about advances in early breast cancer treatment - particularly the CDK4/6 inhibitor ribociclib, now available to Slovenian patients and soon to be produced locally. In this conversation, he explains how novel targeted therapies are reshaping outcomes for patients with hormone receptor–positive disease, with the goal of replacing chemotherapy with more effective and better-tolerated treatment options.
Let’s start with the fundamentals. How has the approach to ER-positive/HER2 negative breast cancer evolved in recent years?
In breast cancer we deal with two main settings - metastatic and early disease - and our goals differ. In metastatic cases, we aim to extend life and preserve quality of life; in early disease, we aim for cure and prevention of recurrence. Over the past few years, we’ve learned that ER-positive breast cancers are driven by an interconnected network involving the estrogen receptor, CDK4/6, and PI3-kinase pathways. Understanding this biology allows us to move away from blunt chemotherapy toward precise, less toxic treatments. Combinations like anti-estrogens with CDK4/6 inhibitors have truly revolutionized patient care, and now we’re seeing these same strategies migrate from advanced disease into the early setting where 80 percent of patients are diagnosed and where we have only one real chance to cure.
That so-called “early window” sounds critical. How do you define high-risk patients who might benefit most from intensified treatment?
We used to classify risk mainly by “geography” - the stage, tumor size, and lymph-node involvement. But now biology often outweighs anatomy. Even node-negative patients with certain genomic features or high-grade tumors can have recurrence risks comparable to node-positive ones. Trials like NATALEE have shown that adding CDK4/6 inhibitors - first abemaciclib for very high-risk cases, now ribociclib for broader, intermediate-risk groups - can reduce recurrence by 30 to 40 percent, even in node-negative disease. This is the third major leap in endocrine therapy, following tamoxifen in the 1970s and aromatase inhibitors in the 1990s.
Are these new risk criteria widely understood among oncologists?
Not yet as much as they should be. For years, “node-negative” meant “good prognosis.” But we now know that’s not always true. Education and communication are crucial. A one-centimeter tumor already contains a billion cells - enough for a few aggressive ones to escape early. If we identify those patients by tumor grade or genomic signature, we can intervene before recurrence decades later. So, the focus must shift from staging to biology.
You are in Slovenia on an important day - the launch of ribociclib for early breast cancer patients in Slovenia. What makes this therapy so effective?
Ribociclib works by blocking CDK4, a key regulator of cell division controlled by the estrogen receptor. When you inhibit CDK4/6 together with hormonal therapy, you essentially freeze cancer cells - they stop dividing and eventually become senescent, allowing the immune system to clear them. Ribociclib is highly selective for CDK4 over CDK6, so it hits the cancer hard while sparing normal cells, making it well tolerated. Given for three years alongside endocrine therapy, it reduces distant recurrence by roughly 30 to 40 percent.
What sets ribociclib apart from other drugs in its class?
Two things: its molecular precision and the strength of the clinical evidence. Biochemically, it has the ideal CDK4-to-CDK6 inhibition ratio, excellent drug exposure, and fewer off-target effects - so patients avoid fatigue or diarrhea seen with less selective agents. Clinically, it’s unmatched: three MONALEESA trials in metastatic disease showed not only longer progression-free survival but also clear overall survival benefit, and now the NATALEE trial confirms benefit in early disease. Because of its tolerability, it’s suitable for up to half of patients with hormone-positive, HER2-negative breast cancer.
And we’re proud that part of the drug’s production happens locally, in Slovenia.
Absolutely. Slovenia played a crucial role in mastering the complex manufacturing steps that ensure global supply. It’s remarkable that such a significant contribution to worldwide oncology care comes from here.
Oncologists often fear side effects and struggle with adherence to long-term therapy. What’s your advice?
The key is partnership with the patient. We can’t just prescribe, we must do it with a patient. That means explaining risks, expected side effects, and management strategies early, so nothing comes as a surprise. Most adverse effects occur in the first six months, then stabilize. Investing extra time early on ensures adherence later. Small adjustments like dose reductions can make therapy sustainable. Ultimately, adherence determines success, because those three years of treatment translate into decades of benefit.
Where do you still see unmet needs for these patients?
Early detection remains crucial - some women are still diagnosed too late. But even after diagnosis, under-treatment is a problem: therapies proven to help aren’t always used. Beyond that, resistance remains a major challenge. The future lies in monitoring minimal residual disease through circulating tumor DNA, so we can detect recurrence before it’s visible on scans and intervene earlier. We’re also working to optimize treatment sequencing - deciding not only what drug to use, but when.
And what about resistance to CDK4/6 inhibitors?
Regarding this I always remember a line in the novel Ana Karenina. It goes like this: All happy families, they look the same. Every unhappy family is unhappy in its own way. The same is with drug resistance. Resistance is complex - there isn’t one pathway. Some tumors lose the RB protein; others switch to CDK2 or activate PI3K/AKT pathways. Because each patient’s mechanism is unique, prevention is better than rescue. By using the most potent combinations early - such as hormonal therapy plus ribociclib, or even triplets that add a PI3K inhibitor - we can hit the cancer in multiple places before resistant clones emerge. It’s about staying one step ahead biologically.
But that brings more toxicity, right?
True, and that’s where improved chemistry helps. As drugs become more selective, combinations become safer. We also need to learn from every patient’s journey through real-world data - so that, like a pilot avoiding turbulence, we can guide each new patient along the smoothest path.
How transformative is liquid biopsy?
It’s remarkable. Instead of invasive biopsies, we can now detect fragments of tumor DNA circulating in the blood. This lets us track tumor evolution, spot resistance mutations, and adjust therapy in real time. It’s already guiding treatment in metastatic disease and soon will in early disease - allowing us to catch recurrences before imaging can. I believe future practice will rely on continuous, DNA-based monitoring rather than waiting for visible progression.
You’re both a clinician and a researcher. What will shape this field in the next five years?
Artificial intelligence and advanced modeling are changing how we design drugs. Machine learning can now identify hidden binding sites on cancer proteins once considered “undruggable.” Organoid and organ-on-chip systems let us test compounds without animals and predict toxicity earlier. These tools, combined with deep biological profiling, will allow us to match each patient with the treatment most likely to produce a strong response. Precision oncology will become not just targeted but personalized in time, selecting the right drug at the right moment.
Before we close, we would be happy to hear your experience with a patient that especially inspired you.
I remember a 66-year-old grandmother who came in with severe back pain and widespread metastases. She was the center of her family’s life - too busy, she said, “to have cancer.” After spinal surgery, we treated her with letrozole and ribociclib. Within weeks, she told me, “Doc, this works. I feel like myself again.” It made me so happy because not long ago, that drug that she was started on was just in clinical trials. That was five years ago. She’s still on treatment, symptom-free, active, living her life without thinking about any other therapy. I think stories like this are important because they show you that you don't necessarily have to be too aggressive with disease and utilize chemotherapy all the time. Cases like hers remind me that targeted therapies can be both powerful and humane, extending life without taking it over. Those are stories that I come to work for, and hopefully I'll have more of them.
That’s inspiring. Especially because we hear oncologists talking about patients' unwillingness for treatment. Yet some still hesitate to take medication.
Most hesitation stems from miscommunication, not defiance. Patients make rational decisions based on what they understand. Our responsibility is to provide clear, compassionate information and to listen. Trust is the foundation. When patients feel supported, they rarely refuse therapy. And as with ribociclib, tailoring dose and duration to each context, rather than a one-size-fits-all approach, makes treatment both tolerable and effective. Life is fragile; every measure that preserves it with good quality is worth the effort.