Key Ideas

Genomic testing is increasingly identifying which early-stage, hormone receptor-positive breast cancer patients can safely skip chemotherapy, even among some node-positive premenopausal women. Adjuvant CDK4/6 inhibitors (abemaciclib, ribociclib) and, for BRCA carriers, olaparib, are now standard additions that improve survival, and trastuzumab deruxtecan has moved into both the neoadjuvant and adjuvant residual-disease settings for HER2-positive disease.

Hormone Receptor-Positive, HER2-Negative Disease: Less Chemo, More Endocrine Intensification

Roughly 70% of breast cancers are hormone receptor-positive and HER2-negative. For low-risk patients (by genomic assay), the standard is endocrine therapy alone; higher-risk premenopausal patients receive chemotherapy, ovarian function suppression, a CDK4/6 inhibitor, and for germline BRCA carriers, olaparib.

A joint analysis of the SOFT and TEXT trials, now with 15- to 16.6-year follow-up, found that exemestane plus ovarian function suppression improved 15-year distant recurrence-free survival over tamoxifen plus ovarian suppression (hazard ratio 0.75), with the largest benefit in grade 3 tumors and high-risk younger patients. This supports ovarian function suppression as standard for premenopausal women at higher recurrence risk, consistent with ASCO guidance.

Genomic testing increasingly determines who needs chemotherapy at all. The 21-gene recurrence score guides postmenopausal decisions clearly (score under 26: no chemo benefit) but leaves more ambiguity for premenopausal, node-negative patients (scores 16-25 may derive similar benefit from ovarian suppression alone as from chemotherapy). For premenopausal women with 1-3 positive nodes, the RxPONDER trial did not show chemotherapy could be omitted for low-risk patients, but whether the benefit these women see is mostly from ovarian suppression rather than chemotherapy itself is being tested in the OFSET trial (results likely a decade away).

This year's OPTIMA trial added further nuance: in patients 40 and older (0-9 positive nodes, ER-positive greater than 10%, HER2-negative), the 50-gene Prosigna test (with ovarian suppression included in the endocrine-only arm for premenopausal patients) identified about two-thirds of patients who did not benefit from chemotherapy, with only small, non-significant differences between chemotherapy and test-directed arms in the low risk patients. This further validates the idea that even node-positive premenopausal patients with low biological risk may not need chemotherapy, although how this gets adopted into practice remains to be seen.

Adjuvant CDK4/6 Inhibitors and Olaparib

Two CDK4/6 inhibitors are now approved in the adjuvant setting. Abemaciclib, based on the monarchE trial (high-risk patients: 4+ positive nodes, or 1-3 nodes plus grade 3, tumor over 5 cm, or high Ki-67), improved both invasive disease-free and overall survival, with a 1.8-percentage-point absolute overall survival benefit at 7 years. Ribociclib, based on the NATALEE trial (broader eligibility including some high-risk node-negative patients), given at a lower dose (400 mg) for 3 years, improved 5-year invasive disease-free survival by 4.5 percentage points overall, with persistent benefit even in high-risk node-negative disease (5.7-point difference) and node-positive disease; overall survival curves are beginning to separate but remain early.

For germline BRCA1/2 carriers, the OlympiA trial (1 year of adjuvant olaparib after neoadjuvant or adjuvant chemotherapy, in patients without a pathologic complete response, or with high-risk residual disease) significantly improved both invasive disease-free and overall survival, reinforcing the importance of routine germline BRCA testing.

Most recently, the lidERA trial tested giredestrant, an oral selective estrogen receptor degrader (SERD), as adjuvant therapy in stage 1-3 ER-positive, HER2-negative disease (without a CDK4/6 inhibitor), and found a significant invasive disease-free survival improvement (hazard ratio 0.70)—in the same range as the CDK4/6 inhibitor trials—with somewhat better tolerability (lower arthralgia-related discontinuation than standard endocrine therapy). How giredestrant will ultimately be positioned relative to CDK4/6 inhibitors in early disease remains to be determined.

HER2-Positive and Triple-Negative Disease: ADCs and Immunotherapy Move Earlier

In HER2-positive early breast cancer, trastuzumab deruxtecan (T-DXd) received two new FDA approvals in May 2026. The DESTINY-Breast05 trial found T-DXd superior to T-DM1 (trastuzumab emtansine) for adjuvant residual disease after neoadjuvant therapy (hazard ratio 0.47, 8.7-point absolute improvement in invasive disease-free survival), with numerically fewer CNS metastases and deaths. The DESTINY-Breast11 trial tested T-DXd in the neoadjuvant setting for high-risk patients (nearly 90% node-positive), finding a pathologic complete response rate of 67.3% with T-DXd followed by THP versus 56% with standard therapy—reaching 83% in hormone receptor-negative, HER2-positive patients specifically. Notably, even four cycles of neoadjuvant T-DXd achieved this high response rate, potentially simplifying decisions about extended adjuvant therapy for patients who achieve a complete response.

In triple-negative breast cancer, the KEYNOTE-522 regimen (carboplatin-paclitaxel, then anthracycline-based chemotherapy, plus pembrolizumab, followed by adjuvant pembrolizumab) remains standard for tumors over 2 cm or node-positive disease. Longer follow-up shows a durable 9-percentage-point improvement in 5-year event-free survival (81% versus 72%) and an emerging overall survival difference, with the clearest benefit concentrated in patients with more extensive residual disease burden (RCB2) after neoadjuvant therapy. Standard post-neoadjuvant management now adds capecitabine for patients with residual disease, and olaparib for BRCA carriers. Still, 15-25% of these patients relapse within 3 years. There are several ongoing trials (SCARLET, testing an alternative chemo backbone; a biomarker-adapted de-escalation trial; and trials testing sacituzumab govitecan or datopotamab deruxtecan in the post-neoadjuvant setting for patients with residual disease) working to further close that gap. 

For Patients

Early-stage breast cancer treatment increasingly relies on genomic testing of the tumor, not just its size or lymph node status, to determine whether chemotherapy is truly needed. This is changing what doctors recommend even for some patients with cancer that has spread to nearby lymph nodes, since a tumor's underlying biology can matter more than how far it has spread. 

For hormone receptor-positive breast cancer, newer pills taken alongside standard hormone therapy (called CDK4/6 inhibitors) have been shown to meaningfully reduce the chance of recurrence and improve survival for higher-risk patients, and for patients who carry an inherited BRCA gene mutation, an additional pill called olaparib provides further benefit.

For HER2-positive breast cancer, a newer antibody-based drug called trastuzumab deruxtecan is now used both before surgery (for higher-risk tumors) and after surgery (for patients with cancer cells remaining after their initial treatment), improving outcomes compared with the prior standard.

For triple-negative breast cancer, adding immunotherapy to chemotherapy before and after surgery has become standard for larger or node-positive tumors, improving how many patients remain cancer-free years later, though there is still meaningful room for improvement, and clinical trials continue to explore ways to do better.

Anyone diagnosed with early-stage breast cancer should ask their care team about genomic testing of the tumor, genetic testing for inherited mutations like BRCA, and whether newer combination therapies or a clinical trial might apply to their specific situation.

Key Takeaways

  • Genomic testing (21-gene recurrence score, Prosigna/ROR) is increasingly used to identify hormone receptor-positive patients, including some node-positive premenopausal women, who do not need chemotherapy.

  • Ovarian function suppression added to endocrine therapy improves long-term outcomes for higher-risk premenopausal women, particularly those with grade 3 tumors.

  • Adjuvant CDK4/6 inhibitors (abemaciclib via monarchE, ribociclib via NATALEE) and olaparib for BRCA carriers (OlympiA) are now standard additions that improve survival in high-risk early breast cancer.

  • The lidERA trial found the oral SERD giredestrant improved invasive disease-free survival in the adjuvant setting, offering a non-CDK4/6-inhibitor option for consideration.

  • Trastuzumab deruxtecan gained two new 2026 approvals in HER2-positive early breast cancer: for adjuvant residual disease (DESTINY-Breast05) and neoadjuvant treatment of high-risk disease (DESTINY-Breast11).

  • The KEYNOTE-522 regimen remains standard for higher-risk triple-negative breast cancer, though 15-25% of patients still relapse within 3 years, motivating several ongoing trials to improve on it.

References

  1. Joint analysis of SOFT and TEXT trials: exemestane plus ovarian function suppression vs tamoxifen plus ovarian function suppression, 15- to 16.6-year follow-up.

  2. OPTIMA trial: Prosigna (ROR) test-directed chemotherapy decisions in HR-positive, HER2-negative early breast cancer. Presented at 2026 ASCO Annual Meeting.

  3. Johnston SR, et al. Abemaciclib in high-risk early breast cancer (monarchE).

  4. Slamon D, et al. Ribociclib in early breast cancer (NATALEE).

  5. Tutt ANJ, et al. Adjuvant olaparib in BRCA-mutated breast cancer (OlympiA). N Engl J Med. 2021.

  6. Bardia A, et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment (lidERA Breast Cancer trial). Presented at 2025 SABCS.

  7. DESTINY-Breast05: Trastuzumab deruxtecan vs T-DM1 in high-risk HER2-positive residual disease.

  8. DESTINY-Breast11: Neoadjuvant trastuzumab deruxtecan-based regimens in high-risk HER2-positive early breast cancer.

  9. Schmid P, et al. Pembrolizumab plus chemotherapy in early triple-negative breast cancer (KEYNOTE-522).