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According to an updated guideline from the American Society of Clinical Oncology (ASCO), breast cancer follow-up and surveillance after primary treatment should be tailored to a patient’s individual risk of recurrence rather than a uniform, one-size-fits-all schedule.¹ The guideline, accepted for publication in Journal of Clinical Oncology, stratifies patients into low-, intermediate-, and high-intensity surveillance groups based on disease stage, biomarker status, and time from diagnosis.

The update was developed by a multidisciplinary ASCO Expert Panel co-chaired by Zeina Nahleh, MD, FACP, chair of the Department of Hematology-Oncology and director of the Maroone Cancer Center at Cleveland Clinic Florida, and Maryam Lustberg, MD, MPH, director of the Breast Center at Smilow Cancer Hospital and chief of breast medical oncology at Yale Cancer Center.¹ ASCO first published breast cancer follow-up guidance in 1997, with subsequent updates in 1999, 2006, and 2013; the 2013 review had concluded that no changes to the 2006 recommendations were warranted. The panel’s systematic review identified only a single randomized controlled trial that directly informed a surveillance recommendation—the mammography schedule—and no randomized trials evaluating follow-up approaches by recurrence risk in early-stage breast cancer, so most recommendations were generated through a formal modified Delphi consensus process across 3 rounds of panel voting.

Low-, Intermediate-, and High-Intensity Surveillance Groups

The low-intensity group includes patients with ductal carcinoma in situ who are not receiving or have completed endocrine therapy, patients with stage I hormone receptor (HR)-positive breast cancer who have completed systemic therapy, and patients with triple-negative breast cancer (TNBC) or HER2-positive breast cancer who are at least 5 years from diagnosis. For this group, ASCO recommends an annual clinical visit, conducted in person or virtually, that may be managed by a survivorship clinic, an oncology advanced practice provider, or a primary care or gynecology clinician.¹

The intermediate-intensity group includes patients with stage I TNBC or HER2-positive disease within 5 years of diagnosis, those with stage II or III TNBC or HER2-positive disease who achieved a pathologic complete response after neoadjuvant therapy, and patients receiving ongoing endocrine therapy. ASCO recommends clinical follow-up with an oncology team or survivorship clinic every 6 to 12 months for 5 to 10 years after diagnosis, with some patients transitioning to low-intensity follow-up after year 5.

The high-intensity group includes patients with TNBC or HER2-positive disease and residual disease after neoadjuvant therapy within 5 years of diagnosis, inflammatory breast cancer within 10 years of diagnosis, carriers of germline BRCA1, BRCA2, or PALB2 mutations, and patients with HR-positive disease receiving endocrine therapy plus a CDK4/6 inhibitor.¹ This group is recommended to have clinical follow-up with the oncology team every 3 to 6 months for up to 10 years after diagnosis, along with chest wall examinations every 6 months.

Mammography Recommendations Draw on the Mammo-50 Trial

For patients treated with breast-conserving surgery in the low-intensity group, ASCO recommends annual mammography for the first 3 years after treatment, followed by surveillance mammography every 1 to 2 years for selected patients 50 years or older with low-risk features (T1, low-grade, node-negative, estrogen receptor–positive tumors) who remain recurrence-free 3 years after diagnosis.^1,2 Patients who prefer to continue annual mammography may do so after discussing the potential benefits and harms with their clinician. In the intermediate-intensity group, annual mammography is recommended for patients treated with breast-conserving surgery, and annual contralateral mammography is recommended after unilateral mastectomy; mammography is not recommended after bilateral mastectomy unless symptoms warrant evaluation. Among patients with high-risk disease, annual mammography is recommended when residual breast tissue remains.

The de-escalated mammography schedule is informed by the Mammo-50 trial, a UK phase 3 noninferiority trial (ISRCTN48534559) that randomized women 50 years or older who were recurrence-free 3 years after breast cancer surgery to annual mammography or less frequent mammography: every 2 years after breast-conserving surgery or every 3 years after mastectomy.² At a median follow-up of 5.7 years, less frequent mammography was noninferior to annual mammography for recurrence-free interval, overall survival, and breast cancer–specific survival, with no major differences in quality-of-life outcomes between the 2 groups.

Blood-Based Biomarkers and ctDNA Not Recommended Outside Clinical Trials

ASCO does not recommend routine complete blood counts, chemistry panels, or tumor markers such as CEA, CA 15-3, or CA 27.29 for surveillance in asymptomatic patients, consistent with the society’s prior guidance. The panel also addressed circulating tumor DNA (ctDNA), stating that ctDNA testing is not recommended for recurrence monitoring outside a clinical trial or research setting.^1,3 The panel noted that although detectable ctDNA can identify patients at higher risk of recurrence, its clinical utility—whether changing treatment in response to a positive result improves outcomes—has not been established, and routine use outside of research could introduce anxiety, unnecessary treatment, and cost without a proven benefit.

Supplemental imaging with breast MRI may be offered through shared decision-making for select patients based on factors including germline mutation status, prior radiation exposure to breast tissue, age younger than 50 years at diagnosis, invasive lobular histology, dense breasts, or cancers not detected by screening mammography. The guideline notes no evidence that MRI surveillance improves overall survival posttreatment, although it may reduce interval cancers in selected higher-risk patients. Routine imaging for distant metastases, including CT, PET, bone scan, liver ultrasound, or chest radiography, is not recommended in asymptomatic patients without symptoms or abnormal clinical findings.

Clinical Context and Limitations

The panel acknowledged that the evidence base for breast cancer surveillance remains limited and cautioned that de-escalating surveillance intensity may feel uncomfortable to some patients and clinicians even where supported by data. ASCO said the risk-adapted approach is intended to better match follow-up intensity to recurrence risk, patient preferences, oncology workforce capacity, and health care costs, and emphasized that shared decision-making conversations should address the purpose of follow-up, recurrence risk, imaging choices, the current lack of evidence for routine tumor marker or ctDNA monitoring, and psychosocial concerns such as fear of recurrence. The panel noted that recommendations will be revisited as additional evidence-based tools become available to further individualize surveillance.

REFERENCES

1. Nahleh Z, Alfano CM, Somerfield MR, et al. Breast Cancer Follow-Up and Surveillance After Primary Treatment: ASCO Guideline Update. J Clin Oncol. Published online July 16, 2026. doi:10.1200/JCO-26-01700

2. Dunn JA, Donnelly P, Elbeltagi N, et al. Annual versus less frequent mammographic surveillance in people with breast cancer aged 50 years and older in the UK (Mammo-50): a multicentre, randomised, phase 3, non-inferiority trial. Lancet. 2025;405(10476):396-407. doi:10.1016/S0140-6736(24)02715-6

3. Lockwood CM, Messersmith HJ, Kim AS, et al. Circulating Tumor DNA Testing in Solid Tumors and Lymphoma: ASCO Guideline. JCO Oncol Pract. Published online June 18, 2026. doi:10.1200/OP-26-00311

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– Beth Bullard, Tragically Beautiful Essays of Love, Loss and Hope

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For patients with hormone receptor–positive metastatic breast cancer, the therapeutic landscape has expanded dramatically.

CDK4/6 inhibitors transformed first-line treatment. Molecularly selected therapies targeting ESR1, PIK3CA and the AKT pathway have created additional endocrine-based options. And perhaps most importantly for HER2-low disease, antibody-drug conjugates have changed the meaning of HER2 expression itself.

Yet real-world treatment often follows a more complicated path.

A large US retrospective study published in Breast Cancer Research and Treatment in 2026 provides an important picture of what happened to patients with HR-positive, HER2-low metastatic breast cancer across up to five lines of therapy.

The analysis included 2,662 patients diagnosed with metastatic disease between 2018 and 2023 using the Flatiron Health Research Database. The investigators examined treatment patterns, real-world progression-free survival and overall survival.

The results illustrate a recurring problem in metastatic breast cancer:

as endocrine options are exhausted, treatment becomes increasingly heterogeneous, chemotherapy use rises, and disease control becomes progressively shorter.

Here are five findings that deserve attention.

Endocrine Therapy Dominated the First Line, but Its Use Declined With Every Subsequent Line

The first-line pattern was predictable.

Overall, 86.2% of patients received an endocrine therapy, containing regimen, and ET plus a CDK4/6 inhibitor was the most frequently used first-line approach.

ET + CDK4/6 inhibition accounted for 57.1% of first-line treatment, while endocrine monotherapy accounted for another 25.6%. Chemotherapy alone was used in 10.1%. The adoption of CDK4/6 inhibitors also increased over time.

First-line ET + CDK4/6 inhibitor use rose from 51.9% in 2017–2019 to 60.7% in 2020–2023, while both endocrine monotherapy and chemotherapy-alone use decreased. But the more interesting story begins after first-line progression.

The proportion receiving ET-containing regimens progressively decreased across lines:

86.2% in LOT1 → 76.7% in LOT2 → 67.2% in LOT3 → 52.0% in LOT4 → 50.3% in LOT5.

That decline reflects what the authors describe as progressive endocrine exhaustion. It is one of the central clinical challenges of HR-positive metastatic breast cancer.

The first endocrine-sensitive phase can sometimes be controlled for years. But after repeated endocrine exposure, acquired resistance increasingly narrows the therapeutic window. The challenge after CDK4/6 inhibitor progression is therefore not simply finding another endocrine drug.

It is determining which tumor remains sufficiently endocrine-dependent to benefit from continued endocrine-based treatment. And that is where modern molecular profiling increasingly matters.

Treatment Became Dramatically More Heterogeneous After the First Few Lines

First-line treatment showed relative consensus. Later-line treatment did not. ET + CDK4/6 inhibition remained the most common treatment in the second and third lines, accounting for 47.0% and 28.2%, respectively.

By the fourth and fifth lines, however, chemotherapy alone became the most frequently used strategy, representing 39.9% of LOT4 and 41.2% of LOT5.

The figure on page 5 illustrates this transition particularly well: the dominant ET + CDK4/6 component contracts substantially from LOT1 through LOT5 while chemotherapy occupies an increasing proportion of later-line treatment.

This is clinically important because later-line HR-positive metastatic breast cancer is not one biological entity. After CDK4/6 inhibitor progression, several mechanisms may drive resistance.

Some tumors remain estrogen-receptor dependent. Others acquire ESR1 alterations. Some harbor actionable alterations in the PI3K/AKT pathway. Others become sufficiently endocrine-resistant that chemotherapy or an antibody-drug conjugate becomes the more appropriate strategy.

The heterogeneity seen in this real-world dataset is therefore not merely prescribing inconsistency. It partly reflects the biology of a disease that becomes increasingly diverse under therapeutic selection pressure.

The modern response to that heterogeneity should increasingly be biomarker-guided sequencing rather than empirical switching between therapies.

Many Patients Reached Chemotherapy After Surprisingly Little Prior Endocrine Therapy

This may be one of the most thought-provoking findings. Among 830 patients who received chemotherapy, only 55.7% had received at least one previous ET-containing line. The median number of endocrine-containing lines before chemotherapy was only one, with an interquartile range of zero to two.

The authors point out that more than 40% of chemotherapy-treated patients had not received an earlier ET-containing regimen, despite recommendations generally favoring sequential endocrine-based therapy before chemotherapy unless endocrine resistance or clinically urgent disease makes that strategy inappropriate.

That observation should be interpreted carefully. It does not demonstrate that chemotherapy was inappropriate. The database did not contain several clinical variables that could explain early chemotherapy use, including:

• visceral crisis or visceral disease burden
• endocrine sensitivity or resistance
• symptom burden
• performance status

Some of these patients may therefore have required chemotherapy because of aggressive or rapidly progressive disease. Still, the finding highlights a broader issue in real-world oncology:

clinical trial algorithms and actual treatment sequences frequently diverge. And as the therapeutic landscape becomes more biomarker-driven, this gap becomes even more important.

Progression-Free Survival Collapsed With Every Additional Line of Therapy

The most visually striking result appears in the Kaplan-Meier curves.

Median real-world PFS was:

• LOT1: 16.3 months
• LOT2: 9.1 months
• LOT3: 6.2 months
• LOT4: 5.3 months
• LOT5: 3.8 months

The Kaplan-Meier curves on page 8 make the therapeutic attrition particularly clear: each successive line produces shorter disease control, with the LOT5 curve falling rapidly and median rwPFS reaching only 3.8 months.

This progressive shortening is clinically familiar. But seeing it quantified across thousands of patients is still sobering. The decline from 16.3 months in the first line to 3.8 months in the fifth line means that median disease control is reduced by more than three-quarters as patients move through successive therapies.

The same pattern appears in overall survival. Median rwOS from metastatic breast cancer diagnosis was 42.4 months, while median rwOS measured from initiation of LOT5 was only 8.2 months. This provides an important argument for optimizing therapy earlier.

A highly effective treatment administered only after several lower-efficacy lines may reach a population with lower performance status, greater disease burden, accumulated toxicity and less time available to benefit.

In other words, line of therapy matters. The efficacy of an agent cannot be considered entirely independently from when the patient receives it.

Fewer Than 4 in 10 Patients Were Alive at Five Years

Perhaps the most important outcome is also the simplest. Median real-world overall survival from metastatic diagnosis was 42.4 months. The estimated five-year survival rate was only 36.9%.

The overall-survival curves on page 7 show the same progressive attrition across treatment lines, with median rwOS falling from 39.9 months at initiation of LOT1 to 25.9 months from LOT2, 16.8 months from LOT3, 11.6 months from LOT4 and 8.2 months from LOT5.

For a disease sometimes described as increasingly chronic, these data provide an important counterbalance. HR-positive metastatic breast cancer may have a relatively favorable prognosis compared with some other metastatic breast cancer phenotypes.

But it remains incurable for most patients. And once endocrine resistance develops and successive treatment lines accumulate, outcomes deteriorate rapidly.

But There Is a Crucial Caveat: This Is Not the 2026 Treatment Landscape

This point is essential when interpreting the study. The cohort reflects treatment delivered mainly between 2018 and 2023.

That means many therapies that now influence HR-positive metastatic breast cancer sequencing were either unavailable, newly introduced or minimally represented. The authors themselves emphasize this limitation.

Trastuzumab deruxtecan’s original HER2-low metastatic breast cancer indication arrived in 2022, and its HR-positive HER2-low/HER2-ultralow indication was subsequently broadened in 2025.

Sacituzumab govitecan entered HR-positive/HER2-negative disease during the study era, while datopotamab deruxtecan was approved later. The authors explicitly note that delayed uptake of ADCs means these therapies were poorly represented in the dataset and that this limits direct applicability to contemporary practice.

The same applies to newer endocrine and targeted options. The paper notes that agents such as imlunestrant, capivasertib and inavolisib were either approved after the study period or not administered to this cohort, reinforcing how rapidly treatment has evolved.

Therefore, the study should not be interpreted as a blueprint for how we should treat HR-positive/HER2-low disease in 2026. It is more useful as something else, a map of the therapeutic attrition that modern therapies are trying to prevent.

HER2-Low Is Particularly Important in This Story

The HER2-low classification became clinically relevant because antibody-drug conjugates demonstrated that tumors without conventional HER2 amplification could still be therapeutically targeted.

In this study, HER2-low was defined as IHC 1+ or IHC 2+/ISH-negative, with no previous evidence of HER2-positive disease. This represents a major conceptual shift.

HER2 expression is no longer merely a binary biomarker separating HER2-positive from HER2-negative disease. It can also function as a drug-delivery biomarker for ADC therapy. And that creates an important question for current practice:

When endocrine therapy begins losing effectiveness, how long should clinicians continue trying successive endocrine-based strategies before moving to an ADC?

The dataset cannot answer that question because the relevant drugs were insufficiently represented. But it demonstrates precisely why the question matters. By LOT4 and LOT5, median PFS had already fallen to approximately five and four months.

A treatment capable of producing more meaningful disease control may therefore have substantially greater clinical value if introduced before profound therapeutic exhaustion.

The Study Also Shows Why Biomarker Testing After CDK4/6 Progression Matters

One striking limitation was the absence of information about important molecular variables, including ESR1 and PIK3CA alterations. In contemporary HR-positive metastatic breast cancer, those variables can substantially alter treatment selection.

This is an important difference between the historical landscape captured in the study and present-day clinical decision-making. The emerging model after CDK4/6 progression is increasingly:

re-biopsy or ctDNA → identify resistance biology → preserve endocrine therapy when biologically appropriate → use mutation-directed treatment when available → transition to ADC or chemotherapy when endocrine benefit is exhausted. That is fundamentally different from simply asking:

“Which chemotherapy should come next?”

The important question is increasingly:

“What is driving resistance now?”

An Important Real-World Strength, and Important Limitations

The study’s size and data source are major strengths.

Flatiron includes data from more than 800 US sites, approximately 75% community practices and 25% academic centers, making the cohort relevant to routine oncology practice rather than only tertiary referral centers.

But several limitations should temper interpretation. The database could miss treatments delivered outside participating systems. Reasons for treatment discontinuation or failure to reach another line were incompletely captured. Visceral disease burden, endocrine resistance, CNS involvement and important genomic alterations were unavailable.

Furthermore, rwPFS relied on physician assessments rather than RECIST, and each treatment-line PFS estimate combined heterogeneous regimens rather than evaluating one specific therapy.

Most importantly, the investigators acknowledge that treatment has evolved so rapidly since 2023 that the results may no longer precisely reflect current standards of care.

There is also an important disclosure: the study was sponsored by AstraZeneca, which also funded medical writing support; several authors were AstraZeneca employees and held company stock or stock options.

That does not invalidate the findings, but it is relevant context—particularly because AstraZeneca co-develops trastuzumab deruxtecan.

The Bottom Line

This real-world analysis tells a straightforward but important story.

Patients with HR-positive, HER2-low metastatic breast cancer generally began treatment with endocrine-based therapy, most commonly combined with a CDK4/6 inhibitor.

But with each successive line:

• endocrine therapy became less dominant
• treatment became more heterogeneous
• chemotherapy use increased
• progression-free survival shortened
• fewer patients remained alive long enough to receive later therapies

Median rwPFS declined from 16.3 months in LOT1 to only 3.8 months in LOT5, and only 36.9% of patients were alive five years after metastatic diagnosis.

The study therefore captures what might be called the therapeutic exhaustion problem of HR-positive metastatic breast cancer. But it also provides a historical benchmark against which the modern era can be judged.

Today, ADCs, next-generation endocrine therapies and biomarker-directed treatments offer opportunities to interrupt this pattern. The challenge is no longer simply extending the number of available lines.

It is making each line more biologically informed, more effective and better sequenced. And in HER2-low metastatic breast cancer, that may ultimately determine whether the steep decline in outcomes seen in this real-world cohort can be meaningfully changed.

Reference

1. Mayer EL, Collin SM, Hillman S, Berrocal-Almanza LC, Sparano J, Lam C. Real-world treatment patterns and outcomes in hormone receptor–positive, HER2-low metastatic breast cancer, 2018–2023: a retrospective, observational, US cohort study. Breast Cancer Research and Treatment. 2026;218:15. Published online July 20, 2026

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-Hafiz Saleh Michika

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From:.breastcancer.org

Tamoxifen is commonly used to reduce the risk of invasive breast cancer or a recurrence of non-invasive disease if someone has been treated for DCIS, LCIS, or atypical ductal hyperplasia.

But because of potential serious risks, including blood clots, endometrial cancer, and stroke, as well as troubling side effects, like hot flashes, many people either don’t start the medicine or stop taking it early. Studies suggest that only about 4–10% of people prescribed tamoxifen after a non-invasive diagnosis take it for breast cancer prevention.

Many researchers and advocates wondered if a lower dose of tamoxifen — 5 mg per day instead of the regular 20 mg — could reduce breast cancer risk without the serious side effects. Many doctors refer to this lower dose as “baby tam.”

In 2023, long-term results from the TAM-01 study found that a 5-mg daily dose of tamoxifen reduced the risk of invasive breast cancer or a recurrence after non-invasive breast disease. This was the first study to show that baby tam could reduce breast cancer risk.

In 2026, a study that combined results from TAM-01 plus two other studies on baby tam found that compared to placebo, low-dose tamoxifen reduced the risk of invasive breast cancer after DCIS or other non-invasive disease. But the benefits depended on menopausal status. Among post-menopausal women, those taking baby tam had a 10-year absolute reduction in invasive breast cancer risk of 11.2%. This means if someone’s personal risk of developing invasive disease after DCIS was 20%, taking baby tam knocked that risk down to 8.8%. Among pre-menopausal women, there wasn’t any difference in risk reduction between women taking low-dose tamoxifen or women taking placebo, though there was a slight reduction in the risk of invasive breast cancer in the opposite breast.

Although the results of TAM-01 and other studies have found that baby tam reduces the risk of invasive breast cancer after non-invasive disease, the studies didn’t look at whether low-dose tamoxifen reduces breast cancer risk in people at high risk of the disease for other reasons, such as strong family history or a BRCA mutation. So doctors are hesitant to recommend baby tam for everyone at high risk.

Experts also have noted that the TAM-01 study found no difference in adherence between the two tamoxifen treatment groups. This means the same number of people taking the standard dose of tamoxifen completed the full course of treatment as people taking low-dose tamoxifen. So if a lower dose doesn’t mean more people stick to their treatment plans, the experts said people should take the standard dose because it has more research backing it and has been used longer.

The side effects of low-dose tamoxifen are similar to those caused by the standard dose: hot flashes, night sweats, vaginal discharge, and fatigue. But studies on baby tam found that low-dose tamoxifen caused fewer and less severe side effects than the standard dose.

In the TAM-01 study, women taking baby tam had one extra hot flash per day compared to women taking the placebo. Earlier studies show that taking the standard 20-mg dose of tamoxifen doubles the number of hot flashes per day.

Rates of blood clots were similar between women taking baby tam and women taking the placebo. This is much different from the three-fold increase in blood clot risk seen in studies using the standard dose of tamoxifen for breast cancer risk reduction. Similarly, rates of endometrial cancer were very low in both treatment groups — only one woman taking baby tam was diagnosed with stage I endometrial cancer. This is about five times lower than rates in studies using standard-dose tamoxifen.

If you’ve been diagnosed with non-invasive breast disease, like DCIS or LCIS, and your doctor recommends medicine to reduce your risk of invasive breast cancer, you may want to ask about low-dose tamoxifen.

If you’re at high risk for breast cancer for other reasons, it’s not clear if baby tam is as effective as the standard dose. But if you’re having severe side effects from the dose of tamoxifen you’re on, you can talk to your doctor about lowering the dose and discuss the risks and benefits of doing so.

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– Mahika Bansal

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