Breast cancer: who decides the treatment sequence

A 36-year-old woman feels a lump in her left breast. The biopsy shows a 3 cm invasive carcinoma, without hormone receptors and without HER2, the so-called triple negative. A fine-needle aspiration of an axillary lymph node also confirms cancer. Her mother had ovarian cancer at age 50. At the first visit, the surgeon proposes mastectomy with implant the following week. No one requested genetic testing, and the patient does not know that starting with systemic treatment is an option. She asks whether she will be able to have reconstruction and whether she will still be able to have children. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The central question is who decides the order of treatment in breast cancer, and why that order should not depend on who sees the patient first. The answer runs through four clues: the tumor type, the genetics, reconstruction with radiotherapy and the patient's preferences. If you play the case of the day in NEXO, you will recognize the logic: each new clue changes the weight of the previous ones.

Key points

• In breast cancer, the order of the steps is a clinical decision, not a fixed routine.
• Triple-negative or HER2-positive tumors, larger or with axillary involvement, often start with systemic treatment.
• The genetic result before surgery changes the surgical choice and can open treatment options afterward.
• The response to neoadjuvant treatment defines the treatment after surgery.
• Radiotherapy and reconstruction need to be planned together.
• The patient's preferences are part of the decision, not a final step.

Why this is a reasoning scenario

Early breast cancer involves several steps that can happen in different orders: surgery, chemotherapy, immunotherapy, targeted therapy, radiotherapy and reconstruction. Each order has consequences. Surgery done first can remove the chance to assess the response to treatment. Reconstruction done without knowing about radiotherapy can fail. Genetic testing requested after surgery can arrive too late to change the surgical choice.

What the scene teaches

The scene shows a reasonable proposal seen from a single place. Operating right away seems to solve the problem. But the tumor has a size and axillary involvement that, in important studies, led to treatment before surgery. The family history suggests a possible genetic variant. And the patient has questions that change the plan: reconstruction and fertility. The reasoning requires asking, before scheduling any procedure, what information is still missing and who needs to be in the decision.

What is not at stake

The text does not detail chemotherapy regimens, surgical techniques or radiotherapy techniques. It also does not discuss metastatic breast cancer or screening. The focus is the order of decisions at the start of care. Each patient's management follows the service protocol and the team's decision.

The team that decides the sequence

In breast cancer, the team usually brings together a mastologist or breast surgeon, a clinical oncologist, a radiation oncologist, a radiologist, a pathologist, a plastic surgeon, a geneticist or genetic counselor and nursing. In some services, psychology and fertility specialists also take part.

The place of the plastic surgeon

A Japanese survey of 429 institutions showed that 72.5 percent offered reconstruction and 61.7 percent could perform immediate reconstruction. Multidisciplinary meetings with plastic surgeons took place in 70.5 percent of the institutions (Shien et al., 2025). The authors point to the lack of plastic surgeons, mistaken ideas about the effect of reconstruction on prognosis and practical difficulties of collaboration between teams as barriers. When the plastic surgeon is not at the meeting, reconstruction tends to be decided late.

Why order of arrival misleads

The patient usually reaches the surgeon first, and the first specialist tends to propose what they know how to do. This is not a lack of care, but a common bias in any field. The multidisciplinary team exists so that the question "what comes first?" is answered by everyone who will be affected by the answer. It is the same principle as interprofessional clinical reasoning.

The first clue: the type of tumor

The biological type of the tumor is the first clue for the order of treatment. A 3 cm triple-negative tumor with axillary involvement behaves very differently from a small tumor with hormone receptors.

The KEYNOTE-522 study

KEYNOTE-522 included 1174 patients with high-risk early triple-negative breast cancer, defined as a tumor larger than 1 cm and up to 2 cm with lymph node involvement, or a tumor larger than 2 cm with or without lymph node involvement. Patients were randomized to receive pembrolizumab or placebo with chemotherapy before surgery, followed by pembrolizumab or placebo afterward. Pathological complete response, that is, the absence of invasive cancer in the breast and lymph nodes at surgery, was 63.0 percent versus 55.6 percent. Event-free survival and overall survival were also better, with hazard ratios of 0.63 and 0.66 (Keytruda label, FDA, 2026).

The regimen and the dose

According to the label, pembrolizumab is used at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks, with chemotherapy for 24 weeks before surgery, and then alone for up to 27 weeks (Keytruda label, FDA, 2026). The label also notes that serious adverse events occurred in 44 percent of patients who received pembrolizumab in the study, and that the drug was discontinued for an adverse event in 20 percent. These numbers need to be part of the conversation with the patient.

What this changes in the scene

The patient in the scene has a 3 cm tumor and axillary involvement, the profile included in KEYNOTE-522. Operating first would remove the chance to know how the tumor responds, information that changes later treatment. An analysis of the 76 participants from Japan in the study found pathological complete response in 53 percent with pembrolizumab and in 48 percent with placebo (Takahashi and colleagues, 2026). The subgroup is small, but it shows that the response varies and needs to be measured.

HER2 positive and residual disease

The same reasoning applies to HER2-positive tumors. According to the summary of a French study, the KATHERINE study showed a 50 percent reduction in the risk of recurrence or death with trastuzumab emtansine, compared with trastuzumab, in patients with residual disease after neoadjuvant treatment. In the Institut Curie study, with patients treated outside clinical trials, dose reduction was needed in 33 percent, mainly due to peripheral neuropathy (De Moura and colleagues, 2025). The lesson is the same: surgery after systemic treatment shows whether there was residual disease, and this finding guides the next step.

The second clue: genetics before surgery

The mother's history of ovarian cancer and the patient's age suggest a possible pathogenic variant in BRCA1 or BRCA2. Knowing this before surgery changes two decisions.

Testing before or after changes the choice

A study of 633 Black women in the United States diagnosed with breast cancer by age 50 compared the timing of genetic testing. Among BRCA variant carriers tested before surgery, 82.8 percent underwent bilateral mastectomy, versus 40 percent of those tested afterward (Roberson and colleagues, 2025). The authors note that American guidelines recommend testing for those diagnosed before age 50 or with triple-negative tumor, and that reasons for not testing include lack of referral by the physician and unfamiliarity with the criteria.

What timely testing can bring

A Danish study of carriers of BRCA1 and BRCA2 variants found that BRCA1 carriers underwent risk-reducing mastectomy of the other side more often than BRCA2 carriers, 66 percent versus 52 percent, and more often received testing within 6 months of diagnosis. Mastectomy of the other side was associated with better distant recurrence-free survival and better overall survival (Kostov et al., 2025). The authors acknowledge a possible selection bias, because healthier women may choose or receive this recommendation more often.

The uncertain result

Genetic testing does not always give a clear answer. A Turkish study of 203 patients with altered BRCA results compared 107 carriers of a pathogenic variant and 96 carriers of a variant of uncertain significance. Bilateral mastectomy was far more common among carriers of a pathogenic variant, 67 percent versus 12 percent (Ökten et al., 2026). A variant of uncertain significance should not be treated as a pathogenic variant, and explaining this difference is a task for genetic counseling.

The family also counts

A genetic result does not affect only the patient. A Mexican study of 246 carriers of pathogenic variants linked to breast cancer showed that almost all of them, 98 percent, said they had shared the result with their family, and that cascade testing of relatives began in 63 percent of families. When recommended, bilateral risk-reducing mastectomy was performed by 37 percent, and removal of the ovaries and fallopian tubes by 48 percent. The barriers cited were financial limitations in 67 percent, lack of a doctor's recommendation in 35 percent and fear in 24 percent (Mesa-Chavez et al., 2024). The authors also point to the lack of cancer genetics specialists and of coverage for the test. The team needs to think not only about the test, but about the path after it.

Genetics also changes treatment later on

The OlympiA study randomized 1836 patients with high-risk HER2-negative breast cancer and a germline BRCA1 or BRCA2 variant to receive olaparib or placebo for 1 year, after surgery, radiotherapy and neoadjuvant or adjuvant chemotherapy (Tutt et al., 2021). In the overall survival analysis, with a median follow-up of 3.5 years, the hazard ratio was 0.68, and invasive disease-free survival at 4 years was 82.7 percent versus 75.4 percent (Geyer et al., 2022). The olaparib label indicates a dose of 300 mg orally twice a day (Lynparza label, FDA, 2025). For the patient in the scene, knowing the genetics early helps plan the surgery and the treatment that comes after.

Olaparib and radiotherapy

OlympiA also shows how sequence matters within the study itself. Patients had to have finished all local treatment, including radiotherapy, between 2 and 12 weeks before entering the study, because radiotherapy interacts with PARP inhibition (Tutt et al., 2021). In practice, the order was systemic treatment, surgery, radiotherapy and only then olaparib. When the team knows the genetics early, it can plan this sequence from the first meeting, instead of discovering it along the way.

The third clue: reconstruction and radiotherapy together

The patient asked about reconstruction. The answer depends on another question: will she need radiotherapy after mastectomy?

Radiotherapy changes reconstruction

A systematic review of 11 studies and 1628 reconstructions, carried out for the Japanese guideline, compared radiotherapy on the expander with radiotherapy after exchange for the implant. Severe complications were similar, 29.1 percent versus 25.3 percent. Reconstruction failure, however, was higher when radiotherapy was given on the expander, 19.9 percent versus 11.8 percent, while severe capsular contracture was lower (Ogita et al., 2025). There is no perfect order, but there are trade-offs the patient needs to know about.

How services deal with this

In the Japanese survey, about 30 percent of institutions interrupted immediate reconstruction if the sentinel lymph node showed metastasis during surgery, and 62.8 percent avoided recommending immediate reconstruction when radiotherapy after surgery was likely. In 94 percent of institutions, reconstruction did not delay adjuvant chemotherapy, but 15 percent modified radiotherapy in reconstructed patients (Shien et al., 2025). These data show why the radiation oncologist and the plastic surgeon need to talk before surgery.

What this changes in the scene

The patient has an involved axilla, which makes radiotherapy after surgery a real possibility. The proposal for implant the following week was made without that discussion. If systemic treatment comes first, the team gains time to assess the response, discuss radiotherapy and plan reconstruction calmly.

Table: the sequence decisions and who makes them

Decision	Central question	Who takes part	Main source
Treatment before surgery	Do the tumor type and size favor starting with systemic treatment?	Oncologist, surgeon, pathologist	KEYNOTE-522
Genetic test	Will the result come out before surgery?	Geneticist, oncologist, surgeon	Roberson et al.
Treatment after surgery	Was there residual disease, and is there a BRCA variant?	Oncologist, pathologist	OlympiA and KATHERINE
Reconstruction	Is radiotherapy likely, and what is the best timing?	Plastic surgeon, radiation oncologist, surgeon	Ogita et al.
Preferences	What does the patient value, and what did she understand?	The whole team and the patient	Herrera de la Muela et al.

The fourth clue: the patient's preferences

The patient asked two questions that were not in the plan: reconstruction and fertility. These questions are not details; they can change the order of treatment.

Shared decision making

A Spanish study of 102 women seen at a multidisciplinary breast unit assessed shared decision making in reconstruction consultations. The patients agreed that they received several options and explanations about advantages and disadvantages, but they felt less confident about their own participation in the decision (Herrera de la Muela et al., 2024). The authors conclude that shared decision making allows combining the evidence and the patient's preferences. Presenting options is not the same as deciding together.

Fertility and time

A 36-year-old patient who will receive chemotherapy may want to discuss fertility preservation before starting. This conversation needs to happen before the first cycle, not after. When the team starts with systemic treatment, the referral to the fertility specialist needs to be part of the plan from the first meeting.

When the patient does not want to decide

Not every patient wants the same degree of participation. Some prefer to decide alone after hearing the options, others prefer to share the decision, and others ask the team to recommend. What matters is to ask and record that preference, and to check what she understood. In the Spanish study, the patients' mean age was 49.8 years, ranging from 22 to 71 years (Herrera de la Muela et al., 2024), which is a reminder that priorities vary greatly from one patient to another. For the patient in the scene, young and with doubts about fertility, this conversation needs to come before the first cycle.

How to organize the start

• Discuss the case with the team before scheduling surgery.
• Check receptors, HER2, size and axilla to decide whether systemic treatment comes first.
• Request the genetic test early when criteria are met, so that the result comes out before surgery.
• Plan reconstruction together with the radiation oncologist and the plastic surgeon.
• Ask the patient about fertility, body image and what she values most.

Risks and reasoning errors

In breast cancer, sequence errors rarely show up on the day. They appear months later, as a reconstruction that fails, a mastectomy on the other side done in a second stage or a lost treatment opportunity. Many resemble the errors described in the text about clinical decision making.

Operating before discussing

Surgery done first in a tumor that would benefit from systemic treatment loses the information from the response. A diagnostic pause before scheduling surgery helps to ask whether the case has already gone to the meeting.

Requesting genetics late

The test ordered after surgery may come too late to change the surgical choice, as shown by the study with young women (Roberson et al., 2025). The question about family history needs to be at the first consultation.

Confusing a variant of uncertain significance with a pathogenic one

Treating a variant of uncertain significance as if it were pathogenic can lead to surgeries that bring no benefit. Interpreting the test requires genetic counseling.

Deciding on reconstruction without radiotherapy

Reconstruction planned without knowing whether there will be radiotherapy is more likely to fail. The radiation oncologist needs to be in the conversation before surgery.

Treating preferences as a detail

Questions about reconstruction and fertility change the order of treatment. Leaving them for the end is deciding by omission. Dealing with these choices is also part of managing diagnostic and therapeutic uncertainty.

Rehabilitation: lymphedema, shoulder and exercise

The treatment sequence does not end at the last radiotherapy session. Axillary surgery, radiotherapy and reconstruction itself leave effects the patient will carry for years, and physical therapy needs to be in the plan from the start. Arm lymphedema is the best-known example: it is disabling, increases costs and worsens quality of life.

For decades, guidelines advised against exercise for women with lymphedema or at risk, based on the idea that exertion would worsen the swelling. Recent systematic reviews have changed that view. Aguilera-Eguía et al. gathered 9 systematic reviews, with 170 primary studies, on exercise in women who already have lymphedema (Aguilera-Eguía et al., 2026). Supervised weight lifting probably reduced the risk of increased arm volume in the long term, with moderate certainty. Aquatic exercise may improve shoulder flexion and abduction when compared with pilates, with low certainty. No adverse events were reported, but the authors note that this does not prove safety, because events were not always defined and recorded.

For prevention, the same group analyzed 8 randomized trials, with 1,131 women at risk of lymphedema (Aguilera-Eguía et al., 2026). Strength training was probably safe, with mild and transient adverse effects, but the preventive effect on lymphedema remained very uncertain. Results on pain, range of motion and grip strength were also inconsistent.

Lymphedema treatment is multimodal. In the review, physical therapy appears as a central piece, with complex decongestive therapy, manual lymphatic drainage, compression and exercise. In practice, this comes down to a few steps:

• assess shoulder and arm before surgery, to have a baseline measurement;
• start shoulder mobilization early, respecting drains and healing;
• measure the arm at follow-up and refer to physical therapy at the first sign of swelling;
• prescribe progressive, supervised strength exercise instead of prohibiting exertion;
• combine compression and skin care when lymphedema already exists;
• include regular aerobic activity in the survivorship plan.

At the team meeting, the question about rehabilitation should appear alongside the others: who will have axillary dissection, who will receive radiotherapy to the axilla and who already has shoulder limitation. These patients need planned referral, not a late consultation when the arm has already swollen.

How NEXO helps train this reasoning

Early breast cancer is a good example of a case where the order of the clues changes the decision. In NEXO, the case of the day works with progressive clues, and training the question "what is missing before deciding the order?" in short cases helps you ask the same question at the team meeting. The method relies on case-based learning.

Three exercises with cases

• Rewrite the scene with the team meeting before surgery and describe the order chosen.
• Imagine the test shows a pathogenic variant in BRCA1. Write what changes in surgery and in later treatment.
• Imagine the patient has a pathologic complete response. List what changes in radiotherapy and reconstruction.

You can also train hypotheses with the text on differential diagnosis with clues. Those who create cases can contribute through the Creators page.

Frequently asked questions

Does every breast cancer start with surgery?

No. Triple-negative or HER2-positive tumors that are larger or have involved axillary nodes often start with systemic treatment, as in KEYNOTE-522. Small hormone receptor-positive tumors usually start with surgery. The decision belongs to the team.

Why do genetic testing before surgery?

Because the result can change the surgical choice, such as bilateral mastectomy, and the treatment afterward, such as olaparib in BRCA variant carriers with high-risk disease.

Does reconstruction delay treatment?

In the Japanese survey, reconstruction did not delay adjuvant chemotherapy at 94 percent of institutions (Shien et al., 2025). The ideal timing depends on radiotherapy and should be decided by the team.

What is pathologic complete response?

It is the absence of invasive cancer in the breast and lymph nodes in the surgical specimen after neoadjuvant treatment. It helps define treatment after surgery.

Who decides the order of treatment?

The team, with the patient. Surgeon, oncologist, radiation oncologist, plastic surgeon, pathologist and geneticist bring different information, and the patient brings what she values.

Final checklist

• I brought the case to the team before scheduling surgery.
• I checked receptors, HER2, size and axilla.
• I requested genetic testing in time to change the surgery.
• I planned reconstruction and radiotherapy together.
• I asked about fertility before chemotherapy.
• I explained the options and checked what the patient understood.
• I recorded the decision, the agreed order and who is responsible for each step.

Want to practice the reasoning with progressive clues? Play the case of the day.

References

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2. Aguilera-Eguía RA, Zaror C, Gutiérrez-Arias R, et al. Effectiveness of Physical Exercise Programs in Reducing Secondary Lymphedema Associated with Breast Cancer: An Overview of Systematic Reviews. J Clin Med. 2026. PMID 42452464.
3. AstraZeneca Pharmaceuticals LP. Lynparza (olaparib), FDA-approved label, version dated 07/25/2025. Official source.
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