Breast cancer treatment landscape
More options and more questions – an evolving treatment and sequencing landscape
Prepared by Lifescience Dynamics | Source base: five expert interviews plus secondary evidence current to May 6, 2026
Executive summary
Breast cancer innovation has rapidly developed throughout the years across HER2+, HR+/HER2-, and triple-negative (TNBC). Although recent therapeutic advances have significantly expanded treatment options, the explosion of novel therapies have led to new questions on treatment selection and sequencing, presenting new challenges to both clinicians and patients.
Expert voice: “There really is a lot going on… There are many more approved therapies and ongoing developments – especially in targeted mechanisms – but there is still a lot to do.” [I1]
Several themes are emerging across the breast cancer landscape. We are seeing de-escalation of treatment in HER2+ disease becoming a new potential trend. In HR+ disease, CDK4/6 inhibitors are moving into the early setting opening up the metastatic landscape and new entrants such as oral SERDs look to be the next backbone therapy. Finally in TNBC, one of the most significant advances has been the rise of ADCs, which have firmly established the modality as a standard of care. The next frontier lies in optimizing patient selection and treatment sequencing, further advancing personalized care. By aligning biomarker screening with treatment decision-making, clinicians can create the best possible conditions for patients to achieve successful outcomes and meet their treatment goals.
1. HER2+ disease: from paradigm stability to patient selection
For more than a decade, 1L metastatic HER2+ breast cancer was anchored by trastuzumab, pertuzumab, and a taxane followed by HER2-directed maintenance, supported by CLEOPATRA. The current inflection is whether trastuzumab deruxtecan (T-DXd) should be used earlier and in which patient population given new clinical data that supports 1L T-DXd plus pertuzumab in HER2+ metastatic disease.
Expert voice: “For patients with low disease burden, especially bone-only disease, I might not choose trastuzumab deruxtecan… For patients with higher disease burden, including visceral metastases or brain metastases, I would favor trastuzumab deruxtecan.” [I5]
The practical implication of this is likely to be patient selection by disease severity and tempo. Patients with visceral crisis, high tumor burden, early relapse after adjuvant HER2 therapy, or brain metastases may justify 1L T-DXd use while patients with indolent, bone-only, or hormone receptor-positive disease may still be candidates for CLEOPATRA-type regimens. However, another key question emerging in the field is how best to approach treatment de-escalation and maintenance strategies following induction therapy. Clinicians are increasingly debating the optimal timing and regimen selection in the post-induction setting, particularly in light of findings from studies such as PATINA and HER2CLIMB-05 which provide potential chemo/ADC free maintenance regimens.
Expert voice: “One interesting idea is to use trastuzumab derustecan for six or seven months, then switch to maintenance therapy” [I5]
Another complicating factor is the management of brain metastases. HER2CLIMB established tucatinib-based therapy with trastuzumab as a key CNS-active regimen, while DESTINY-Breast12 provided prospective evidence supporting T-DXd activity in patients with both stable and active brain metastases. These data further complicate treatment selection, particularly as T-DXd may increasingly be used upfront in the 1L setting. One expert emphasized the value of novel treatments’ ability to pass the blood-brain barrier because HER2+ patients often progress with CNS metastases.
Expert voice: “Therefore, we like to use medications that can cross the blood-brain barrier and demonstrate efficacy there. That’s one reason we choose some of these treatments. [I1]
Finally, the triple-positive (HR+/HER2+) subgroup adds another layer of complexity to an already nuanced HER2+ treatment landscape. PATINA demonstrated that adding palbociclib to anti-HER2 therapy plus endocrine treatment in the post-induction setting improved median PFS from 29.1 to 44.3 months, supporting a dual-pathway maintenance strategy for this specific patient subset. While this offers an important new option after initial therapy, it also raises further questions around induction choices and optimal sequencing, particularly given the expanding range of available regimens.
Overall, the expanding treatment landscape creates a favorable environment for patients. However, to fully realize this potential, the community will need to continue refining patient selection and treatment sequencing to deliver truly personalized care in this era of therapeutic abundance.
2. HR-positive/HER2-negative disease: endocrine backbones are being rebuilt
CDK4/6 inhibitors plus endocrine therapy have long been established as the standard of care in the 1L HR+ setting. However, their widespread use has also created a large post-CDK4/6 population characterized by acquired endocrine resistance. ESR1 mutations are uncommon prior to endocrine exposure but become increasingly prevalent in later lines, with ASCO guidelines recommending testing at recurrence or progression. In recent years, the US FDA has approved several ESR1-directed therapies, primarily oral SERDs, which have made testing clinically actionable. In practice, experts described ESR1 testing as increasingly standard, but still operationally uneven due to reimbursement, assay choice, tissue availability, and turnaround time.
Expert voice: “We cannot wait two or three weeks to know whether a patient has a mutation.” [I3]
Oral SERDs and next-generation ER-directed therapies are attractive because they avoid painful fulvestrant IM injections and can provide continuous ER suppression. However, experts were cautious about overvaluing monotherapy gains which have supported approvals of recent oral SERDs.
Expert voice: “ PFS improved from about two months to four months. That’s statistically significant, but clinically, patients may not perceive it as meaningful.” [I2]
This is pushing the field toward combination strategies, particularly SERDs or other ER degraders paired with targeted therapies. Combination strategies are likely to benefit from the several targeted agents have been approved in recent years, including capivasertib and inavolisib, underscoring how PI3K/AKT pathway targeting is further segmenting the post-CDK4/6 setting by molecular alteration. However, many of these approaches depend on confirming the relevant mutation before treatment can begin. This is where ctDNA testing may play an increasingly important role in its ability for rapid and more continuous testing, although interviews highlighted a persistent gap between detection and clinical action. Tissue testing remains the gold standard, and experts continue to highlight concerns around the relative sensitivity and specificity of ctDNA-based approaches.
Expert voice: “I still think tissue testing is much better than liquid biopsy for ESR1 mutations. In my own experience, I have patients where I tested with two different liquid biopsy brands, in one, I found the mutation. With the other, I did not find the mutation. But when I tested tissue, I found the mutation. [I3]
Adherence represents another underappreciated challenge. While new oral therapies (e.g. SERDs) offer convenience, many patients are also managing medications for diabetes, hypertension, hyperlipidemia, and other comorbidities increasing pill burden. Experts noted that even a 15–20% adherence gap could have meaningful clinical implications.
Expert voice: “Absolutely, adherence will be an issue. Patients may forget doses, have unreported drug interactions, get the timing wrong or inconsistently… Even a 15-20% adherence issue is significant to impact outcomes” [I1]
Thus, despite the advancements and the growth of treatment options, the increasingly hyper-fragmented market highlights the unmet need for faster and more accurate testing to guide selection. Therefore, developers may likely benefit from establishing a foothold in the ever-growing fragmented space while looking to expand towards an all-comer approach that takes into account a diverse treatment sequence landscape.
3. TNBC: biomarker-positive progress, biomarker-negative need
TNBC remains the subtype with the greatest unmet need for durable disease control, despite rapid advances in recent years. A key development has been the emergence of PD-L1 status as a major determinant of 1L treatment selection, with pembrolizumab plus chemotherapy now established as the mainstay for patients with PD-L1+ metastatic disease. Germline BRCA testing remains important for PARP inhibitor eligibility, while ADCs such as sacituzumab govitecan and datopotamab deruxtecan may potentially become the SoC backbone therapy for TNBC.
Nevertheless, important gaps remain, with experts converging on three key innovation priorities. First, earlier-line regimens need to deliver greater durability without compounding toxicity. Second, treatment after immunotherapy and ADC exposure remains poorly defined. Third, biomarker-negative disease still needs effective options beyond chemotherapy. Sacituzumab govitecan established a survival benefit in previously treated metastatic TNBC, and ADCs are now expected to enter the 1L metastatic setting. Yet clinicians still emphasized that after ADCs, later-line options are often limited and outcomes remain poor.
Expert voice: “Unlike other subtypes, there is still a need for biomarker driven selection for TNBC patients especially due to poor outcomes… Later line options are limited to chemotherapy with poor efficacy” [I2]
Overall, several advances have improved outcomes for TNBC patients, a group with historically poor outcomes; however, defined treatment sequencing and later-line options remain elusive. Therefore, developers will need to expand beyond ADCs and look at new modalities, such as bispecifics, to demonstrate activity in clinically relevant prior-treatment contexts and not only clean earlier-line populations.
4. ADCs: the backbone class with the biggest sequencing gap
ADCs are increasingly being integrated across breast cancer subtypes and treatment lines, shifting from isolated late-line therapies and becoming a core treatment option across multiple breast cancer subtypes. Trastuzumab deruxtecan is moving earlier in HER2-positive disease, and has now expanded to cover HER2-low and -ultralow settings, substantially broadening the population eligible for HER2-directed ADC therapy. In TNBC, sacituzumab govitecan has become established after prior therapy, while additional TROP2-directed ADCs continue moving toward earlier-line settings. In HR+/HER2- disease, while ADCs are still typically used after endocrine options are exhausted, high tumor burden may potentially accelerate ADC use even further up. As more ADCs gain approval and additional agents continue to emerge, determining how best to sequence these therapies is becoming one of the central questions in breast cancer management. With optimal sequencing remaining one of the most important unresolved questions in breast cancer treatment, clinicians varied in their willingness to use sequential ADCs. Some favored ADC-after-ADC strategies when targets or payloads differed, while others preferred introducing chemotherapy intervals or waiting for stronger evidence before routinely sequencing ADCs.
Expert voice: “I think sequencing ADCs can theoretically work, especially if you are changing the payload […] but my clinical experience was not very positive. The PFS on the second ADC was very low, often only two or three months” [I3]
Expert voice: “Maybe if we change both the target and the payload, we could find some clinical benefit.” [I5]
Several experts also highlighted concerns around potential cross-resistance between topoisomerase I–based payloads. Real-world evidence suggests that sequential trastuzumab deruxtecan and sacituzumab govitecan can maintain activity in some patients, although the second ADC often demonstrates reduced efficacy compared with the first.
Expert voice: “Many ADCs use topoisomerase-based payloads, so theoretically there could be cross-resistance.” [I4]
Resistance to ADCs may develop through multiple mechanisms, including changes in target expression, reduced intracellular payload delivery, evolving tumor biology, drug resistance pathways, or treatment-limiting toxicity.
Expert voice: “The key question is understanding why tumors progress after ADCs. What are the resistance mechanisms?” [I3]
Importantly, experts suggested that future ADC differentiation will likely depend on more than target selection alone. Clinically meaningful differentiation may instead depend on activity after prior ADC exposure, a manageable chronic toxicity profile, CNS activity, administration convenience, validated biomarker strategies or ease of reimbursement.
Experts were also skeptical of purely “me-too” ADCs targeting the same antigens with highly similar payloads unless they demonstrated either improved tolerability, broader eligibility, or activity after prior ADC exposure. Novel targets including B7-H4, bispecific ADCs, and non-topoisomerase payload strategies were frequently cited as promising approaches to move beyond the increasingly crowded HER2 and TROP2 landscape. Across breast cancer subtypes, the central challenge is shifting from proving whether therapies work to understanding where they fit within increasingly complex treatment sequences.
Expert voice: “I don’t think just changing the payload or the payload charge is enough. The key question is whether we can also change the receptor target or use bispecific ADCs.” [I3]
Expert voice: “Maybe if we change both the target and the payload, we could find some clinical benefit [however,] I would like to see proof-of-concept Phase 2 data or even a patient series showing clinical benefit before becoming comfortable with ADC-after-ADC sequencing.” [I5]
5. Cross-cutting implications for stakeholders
For clinicians, the practical shift is from line-by-line algorithms to tailored treatment planning at varying progression points. Clinicians should reassess whether the patient is still expressing the same target, whether a new resistance marker has emerged or whether the next therapy is tolerable enough for the intended duration. This creates greater need for shared decision-making around toxicity, treatment goals, monitoring burden, and adherence demands
For biopharma developers, differentiation will increasingly require demonstrating where a therapy fits within real-world treatment sequences rather than simply outperforming past standard of care in isolated lines of therapy. For diagnostics manufacturers, the opportunity is evolving from one-time biomarker testing toward longitudinal disease monitoring capable of informing treatment decisions throughout the patient journey.
Expert voice: “If you detect something early but the patient is asymptomatic, what do you do? That’s still unclear.” [I1]
Expert voice: “ctDNA testing can be logistically and financially unrealistic for some healthcare systems” [I5]
For patients and advocates, the growing number of treatment options represents both an opportunity and a burden. Shared decision-making tools will increasingly need to translate complex therapeutic choices into understandable tradeoffs involving speed and depth of response, CNS control, clinical visit burden, oral adherence requirements, side effect profiles, financial burden, and preservation of future treatment options
Conclusion
Breast cancer treatment is entering a new era defined not by a shortage of therapies, but by the growing complexity of how best to use them. At the same time, these advances have introduced new challenges around sequencing, biomarker interpretation, long-term tolerability, and treatment personalization. Increasingly, the key clinical question is no longer simply whether a therapy is effective, but which patient is most likely to benefit and at which part of their treatment journey. Earlier use of highly active therapies may deepen responses and delay chemotherapy, but also creates downstream uncertainty around resistance mechanisms, retreatment strategies, and preservation of future options. The therapies and strategies most likely to shape future care will be those that can demonstrate not only strong efficacy, but also clear positioning within increasingly complex treatment sequences and meaningful value for patients over the long term.
Selected sources
[1] World Health Organization. Breast cancer fact sheet. Updated April 2026.
[2] NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2026.
[3] U.S. FDA. Fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable/metastatic HER2+ breast cancer. 2025.
[4] Swain SM et al. CLEOPATRA end-of-study analysis. Lancet Oncology. 2020.
[5] Lin NU et al. Tucatinib plus trastuzumab/capecitabine in HER2+ MBC with brain metastases. J Clin Oncol. 2020.
[6] Harbeck N et al. DESTINY-Breast12: T-DXd with/without brain metastases. Nature Medicine. 2024.
[7] Metzger O et al. PATINA: palbociclib with anti-HER2 and endocrine therapy. NEJM. 2026.
[8] FDA elacestrant approval, 2023; Burstein et al. ASCO ESR1 testing rapid update. JCO. 2023.
[9] FDA imlunestrant approval for ER+/HER2-, ESR1-mutated advanced breast cancer. 2025.
[10] FDA capivasertib plus fulvestrant approval, 2023; Turner NC et al. CAPItello-291. NEJM. 2023.
[11] FDA inavolisib plus palbociclib/fulvestrant approval for PIK3CA-mutated HR+/HER2- disease. 2024.
[12] FDA T-DXd approval for HR+, HER2-low/ultralow disease, 2025; Modi S et al. DESTINY-Breast04. NEJM. 2022.
[13] Bardia A et al. ASCENT: sacituzumab govitecan in metastatic TNBC. NEJM. 2021.
[14] NCI summary of KEYNOTE-355 in advanced TNBC, 2022; KEYNOTE-522 perioperative pembrolizumab updates, 2024.
[15] Huppert LA et al. Sequential T-DXd and sacituzumab govitecan in HER2-low metastatic breast cancer. npj Breast Cancer. 2025.
[16] Valle I et al. ADC mechanisms of resistance and future therapeutic perspectives. npj Breast Cancer. 2025.
[I1] Interview with US Senior Clinical Fellow
[I2] Interview with US Medical Oncologist
[I3] Interview with Spain Medical Oncologist
[I4] Interview with US Oncologist Hematologist
[I5] Interview with Spain Medical Oncologist
