Part XI · Hormone receptor-positive, HER2-negative disease · Chapter 59

Adjuvant chemotherapy and the genomic assay decision

Which decisions in this subtype rest on a randomised comparison against usual care, and which rest on a subgroup, a margin or a population nobody enrolled.

1 · Clinical and genomic risk assessment

Risk in this subtype runs on two axes that are routinely collapsed into one. The anatomic axis is tumour size and nodal burden. The biological axis is grade, proliferation and the output of a multigene assay. They correlate weakly and they answer different questions.

This chapter is about how to approach the patient. It covers what to measure, what to give, to whom, for how long, and what to do once treatment stops. The randomised trial record it draws on lives next door and is not repeated here. Adjuvant endocrine therapy is in Adjuvant endocrine therapy. Adjuvant CDK4/6 inhibition is in Adjuvant CDK4/6 inhibition. Preoperative systemic therapy in this subtype is in Neoadjuvant therapy. Adjuvant PARP inhibition is in Adjuvant PARP inhibition for germline carriers. Where a decision below rests on one of those records, the text points forward rather than restating it.

The two axes are not academic, because they have been used to define eligibility for different treatments. monarchE enrolled on clinicopathological criteria1. NATALEE enrolled on anatomic stage instead2. Only NATALEE accepted a high-risk genomic assay result, and only as one way for grade 2, node-negative stage IIA disease to qualify3. The population column of the table in Scope, and why four trials of one drug class gave different answers is where the difference is legible.

The anatomic axis also does most of the work in predicting late events. Size and nodal status still stratify distant recurrence risk between years 5 and 20. The figures are in Late recurrence risk and surveillance implications4. Nothing in routine use has superseded them.

Two measurement cautions belong with all of this. Ki-67 is the least reproducible of the routine variables, and the scoring conventions that make it usable are set out in5 and6. And a genomic assay reports a risk estimate conditioned on the treatment the validation cohort received, which is developed in Prognostic and predictive assays and somatic profiling. Tools that combine the recurrence score with clinicopathological features report a different quantity again7.

2 · Genomic assays and the decision to omit chemotherapy

Early disease · HR+/HER2- · adjuvant

Choosing the intensity and the duration of endocrine treatment

Can the decision to give chemotherapy be made on biology rather than on anatomy?

Rationale
Node count and tumour size measure how long a cancer has been growing, not how much it depends on oestrogen. A genomic assay measures the second, which is what predicts whether cytotoxic treatment adds anything to endocrine treatment.
Experiment
Randomised trials that assigned chemotherapy by a genomic score rather than by stage, in node-negative and then node-positive disease, with survival as the endpoint.
Finding
A large fraction of this cell can omit chemotherapy without losing disease control, and the exceptions cluster by age and menopausal status rather than by score alone.
Limitation
The assays were validated on populations treated with the endocrine therapy of their era, and the age effect is confounded with ovarian function, so the benefit attributed to chemotherapy may partly be the benefit of chemotherapy-induced menopause.
Next question
If a score taken once before treatment can allocate chemotherapy, can the tumour's own response to a short course of endocrine therapy allocate it better?

TAILORx RxPONDER MINDACT

Can the response to treatment be used to allocate treatment, rather than the baseline alone?

Rationale
A baseline assay predicts; a short course of endocrine therapy tests. A tumour whose proliferation collapses under two weeks of an aromatase inhibitor has demonstrated the dependence the assay was trying to infer.
Experiment
Response-adapted designs that give a brief endocrine exposure, measure the change in proliferation, and route patients to chemotherapy or to endocrine treatment on what they see.
Finding
Response separates the population, and the endocrine-responsive group does well on endocrine treatment alone.
Limitation
A dynamic marker predicts outcome in a cohort that has already been selected on it, so the comparison is against a historical expectation rather than against the same patients treated the other way.
Next question
Does adding CDK4/6 inhibition to the induction course change who looks responsive, and is that change real or an artefact of a drug that suppresses proliferation in everyone?

WSG-ADAPT HR+/HER2− WSG ADAPTcycle

What did the cohorts that built the genomic assays actually randomise?

Rationale
A genomic assay that allocates chemotherapy has to be validated on material from patients who were randomised to receive it or not. The archival cohorts that made the recurrence score possible were trials run for a different purpose, and their design constrains what the score can be read to establish.
Experiment
Retrospective assay of banked tumour from randomised adjuvant trials. Tamoxifen against placebo in node-negative receptor-positive disease, chemotherapy added to tamoxifen in the same population, and chemoendocrine therapy against endocrine therapy alone in node-positive postmenopausal disease.
Finding
The score is prognostic in the endocrine-treated arms and predicts chemotherapy benefit in the randomised comparisons, with the benefit concentrated at the high end of the range. The node-positive cohort established that the same relationship holds when nodes are involved.
Limitation
These are retrospective analyses of prospectively randomised trials, which is stronger than a cohort and weaker than a trial designed to answer the question. The chemotherapy regimens are decades old and no longer given, so a benefit measured against them may not transfer. The assay was developed on some of the same material it is validated against.
Next question
Does a score built on the biology of endocrine responsiveness predict benefit from a regimen it never saw?

NSABP B-14 NSABP B-20 SWOG-8814 / INT-0100 WSG-PlanB

This is the chapter's own question, in the two forms the trials were built to answer. The first asks whether a score measured once before treatment can allocate chemotherapy. The second asks whether the tumour's behaviour under a short course of endocrine therapy allocates it better.

The predictive claim came before any of the randomised trials. It was made retrospectively, inside three trials designed to answer something else.

The archival cohorts in which the 21-gene assay's predictive claim was first made.

Each row is a randomised trial repurposed, not a trial of the assay.

TrialPopulationExperimental vs controlResult
SWOG-8814 / INT-010081558Postmenopausal women with hormone receptor positive, node positive breast cancer.CAF followed by tamoxifen, or CAF with concurrent tamoxifen, versus tamoxifen alone.Disease-free survival was longer with CAF plus tamoxifen than with tamoxifen alone, adjusted hazard ratio 0.76, 95 percent CI 0.64 to 0.91, p=0.002. Sequential CAF then tamoxifen was not significantly better than concurrent tamoxifen, hazard ratio 0.84, 95 percent CI 0.70 to 1.01, p=0.061.
NSABP B-2092306Patients with axillary lymph node-negative, estrogen receptor-positive breast cancer treated surgically.Methotrexate and fluorouracil plus tamoxifen, or cyclophosphamide, methotrexate and fluorouracil plus tamoxifen, versus tamoxifen alone.Five-year disease-free survival was 90 percent with methotrexate and fluorouracil plus tamoxifen and 89 percent with CMF plus tamoxifen, versus 85 percent with tamoxifen alone (P=.01 and P=.001).
NSABP B-14102644Women with operable breast cancer, histologically negative axillary nodes, and estrogen-receptor-positive tumours of at least 10 fmol.Tamoxifen 10 mg twice daily after surgery versus placebo.Disease-free survival at four years was 83 percent with tamoxifen and 77 percent with placebo (P<0.00001).

Each of the three contributed a different piece, and none of them was designed to. The randomised comparison in NSABP B-14 was tamoxifen against placebo, so the assay work used one arm of it and could show only that the score is prognostic under tamoxifen11. NSABP B-20 randomised chemotherapy added to tamoxifen, so it could ask about an interaction, and reported one12. SWOG-8814 / INT-0100 carried the same structure into postmenopausal node-positive disease with an anthracycline regimen13. The parent trial had randomised chemotherapy followed by tamoxifen against tamoxifen alone, and chemotherapy given before tamoxifen against the two given together8. Prognostic and predictive are different claims, and only the second and third rows were built in a way that could support the predictive one.

What all three share matters more than what separates them. Each measured the score in banked blocks from a minority of the enrolled patients, and tissue availability is not a random event. Each conditioned the score on tamoxifen alone as the endocrine backbone, because that was the treatment of the era. The score was later shown to be prognostic under anastrozole, in node-negative and node-positive disease, in TransATAC14. That established risk under an aromatase inhibitor, not chemotherapy benefit. Nobody has recalibrated the chemotherapy thresholds against an aromatase inhibitor or against tamoxifen with ovarian suppression, which is what the patient in front of you will receive. That is a measurement problem rather than a biological one, and it propagates into every prospective trial below, all of which inherited the thresholds.

The same archival route produced the score's other associations. In node-negative NSABP trials it was associated with locoregional recurrence as well as distant recurrence15. Prognostic estimates were better when the score was combined with clinicopathological information than when it was combined with the online Adjuvant calculator16. Registry and prospective cohorts then allocated treatment by the score. In PlanB, 348 patients with a score of 11 or less omitted chemotherapy, and their three-year disease-free survival was 98%17. In a registry of node-positive disease with micrometastases or one to three positive nodes, outcomes with a score below 18 supported endocrine therapy alone18.

The prospective trials that tested assay-guided and response-guided chemotherapy omission.

TrialPopulationExperimental vs controlPrimary endpointResultOverall survival
WSG-ADAPT HR+/HER2−192290 · reportedPatients with hormone receptor-positive HER2-negative early breast cancer and no more than three involved lymph nodes.Endocrine therapy alone for recurrence score 12 to 25 with endocrine response versus endocrine therapy alone for recurrence score 11 or lower.Noninferiority of five-year invasive disease-free survival in the experimental arm compared with the control arm.Five-year invasive disease-free survival was 92.6% in the experimental arm versus 93.9% in the control arm, and the one-sided 95% lower confidence limit of the difference was -3.3%, establishing prespecified noninferiority.Five-year overall survival was 97.3% in the experimental arm versus 98.0% in the control arm.
MINDACT206693 · reportedearly breast cancer with up to three positive nodes, staged for clinical risk by a modified Adjuvant! Online and for genomic risk by the 70-gene signature; 6,693 enrolled and the 1,497 at high clinical and low genomic risk randomisedchemotherapy vs no chemotherapy in patients whose clinical and genomic risk disagreed5-year distant metastasis-free survival without chemotherapy in patients at high clinical and low genomic risk, against a non-inferiority boundary of 92%5-year distant metastasis-free survival without chemotherapy in the primary test population of 644 patients was 95.1% (93.1-96.6), above the 92% boundary. In the randomised intention-to-treat comparison, 8-year distant metastasis-free survival was 92.0% with chemotherapy and 89.4% without, HR 0.66 (0.48-0.92)not reported in the updated analysis
RxPONDER215083 · reportedhormone receptor-positive, HER2-negative disease with one to three positive axillary nodes and a 21-gene recurrence score of 25 or lower; 33.2% premenopausalendocrine therapy alone vs chemotherapy followed by endocrine therapyinvasive disease-free survival, and whether the chemotherapy effect varied with the recurrence scorethe chemotherapy effect differed by menopausal status, interaction P=0.008. Postmenopausal 5-year invasive disease-free survival 91.9% with endocrine therapy alone against 91.3% with chemoendocrine therapy, HR 1.02 (0.82-1.26), P=0.89. Premenopausal 89.0% against 93.9%, HR 0.60 (0.43-0.83), P=0.002. The relative benefit did not increase as the score increasednot reported at the third prespecified interim analysis
TAILORx226711 · reportedhormone receptor-positive, HER2-negative, axillary node-negative breast cancer; 10,273 enrolled and the 6,711 with a midrange 21-gene recurrence score of 11 to 25 randomisedendocrine therapy alone vs chemotherapy followed by endocrine therapy, in patients with a recurrence score of 11 to 25invasive disease-free survival, non-inferiority designendocrine therapy was non-inferior to chemoendocrine therapy, HR 1.08 (95% CI 0.94-1.24), P=0.26; 9-year invasive disease-free survival 83.3% against 84.3%. Chemotherapy benefit varied with recurrence score and age (P=0.004), with some benefit in women aged 50 or younger scoring 16 to 259-year overall survival 93.9% with endocrine therapy and 93.8% with chemoendocrine therapy
WSG ADAPTcycle231684 · ongoingintermediate-risk HR-positive, HER2-negative early breast cancer selected by a 21-gene recurrence score and by endocrine response measured as post-endocrine Ki-67; 5292 screened and 1684 randomised at 85 German sitesribociclib plus an aromatase inhibitor, with a gonadotropin-releasing hormone agonist in premenopausal women, vs chemotherapy followed by endocrine therapyinvasive disease-free survivalnot yet reported; local against central agreement for post-endocrine Ki67 at or below 10% was 80.5%, 95% CI 79.0 to 82.1not yet reported

Four reported trials and one still running, and they converge on one finding. In node-negative or limited node-positive hormone receptor-positive disease, a large fraction of patients can be treated with endocrine therapy alone without a measurable loss of distant disease control over the follow-up so far accrued. That is the finding. Everything else in the table is a difference in how it was established.

Those differences are design, population and endpoint, not assay performance. TAILORx randomised chemotherapy against no chemotherapy inside a midrange score band in node-negative disease, and was powered as a non-inferiority comparison22. MINDACT randomised only the patients whose clinical and genomic risk disagreed, and its primary question was a single-arm rate tested against a fixed boundary, with the randomised comparison secondary24. RxPONDER moved to one to three positive nodes and capped the score at 2521. WSG-ADAPT HR+/HER2− compared two prospectively defined groups rather than two randomised ones, because allocation followed biology19. The assays differ too, with a 70-gene signature in MINDACT and a 21-gene score elsewhere, on thresholds that are not interchangeable. And the endpoint differs, because a distant metastasis-free survival endpoint and an invasive disease-free survival endpoint do not count the same events. The second counts second primaries and non-breast deaths, which dilutes a chemotherapy effect in an older population and inflates it in none.

The decision in node-negative disease rests on TAILORx. It is the only row that randomised the thing a clinic would otherwise do against the thing it would otherwise omit. It did so in the population where the question is actually asked, with enough events to bound the difference.

RxPONDER is the one that did not settle its question, and the reason sits in the interaction rather than in either arm. Chemotherapy benefit differed by menopausal status, with an interaction p value of 0.00821. The two strata point in opposite directions. A single hazard ratio for that trial would describe nobody. One sentence in that report matters more than the headline. The relative chemotherapy benefit did not increase as the recurrence score increased. In node-positive premenopausal women the assay identified who was at risk. It did not identify who benefited from chemotherapy.

Read alongside TAILORx, where the residual chemotherapy signal also sat in women aged 50 or younger, that is the same finding twice. MINDACT looked in the same place, reporting an exploratory analysis by age in its update20. Age and menopausal status travel together, and no trial in this table randomised ovarian suppression. The benefit attributed to chemotherapy in young women cannot be separated from the benefit of chemotherapy-induced menopause.

WSG-ADAPT HR+/HER2− answers the second question and answers it in a form that needs care. Three weeks of preoperative endocrine therapy separated the population, with central Ki-67 read before and after. The endocrine-responsive midrange group then did as well on endocrine therapy alone as the low-score control group19. The comparison was between two arms defined by the marker, so nobody with an endocrine-responsive midrange tumour was treated the other way. The response rate also depends on which drug was given, at 78.1% on an aromatase inhibitor against 41.1% on tamoxifen. Endocrine response as measured here is a property of the test as much as of the tumour.

WSG ADAPTcycle is still running. It asks whether ribociclib with an aromatase inhibitor can take the place of the chemotherapy that a recurrence score and an endocrine response test would otherwise mandate. That is the only substitution question in the table. Its reported concordance work is the part to read now. Local and central Ki-67 disagreed on the endocrine-response call often enough that 13.1% of patients called responders locally were non-responders centrally23. A response-guided strategy is only as portable as the assay that defines response.

All five rows should be read alongside the non-inferiority methods in Clinical trials and evidence interpretation and specifically Designing de-escalation trials and the non-inferiority margin problem. Three things the table cannot give you are worth naming. Nobody randomised assay use against no assay use, so the value of testing itself is inferred from the outcomes of the tested. Nobody enrolled four or more positive nodes into an omission question. And the overall survival column is where the gap shows, because the node-positive trial has not reported it and this subtype recurs for twenty years Late recurrence risk and surveillance implications.

Caution

A trial that declares endocrine therapy non-inferior has not shown that chemotherapy does nothing. It has shown that the difference is smaller than a margin chosen in advance. The MINDACT intention-to-treat comparison makes the point concretely, because its eight-year distant metastasis-free survival favoured chemotherapy inside a design whose primary question was a single-arm rate against a fixed boundary20. The general form of this error is set out in Designing de-escalation trials and the non-inferiority margin problem.

Caution

The premenopausal RxPONDER result is widely read as showing that chemotherapy works in young node-positive women with low genomic risk. The flat relationship between score and benefit is compatible with a different reading, which is that some of what chemotherapy delivered was ovarian suppression21. The trial did not randomise suppression, so it cannot separate the two. A patient offered chemotherapy on this evidence should be told that ovarian suppression is the alternative hypothesis, not a consolation prize.

3 · Chemotherapy selection when it is indicated

Choosing the intensity and the duration of endocrine treatment, continued

Which chemotherapy regimen, for the minority of this subtype who need one?

Rationale
The adjuvant chemotherapy backbone was built before subtype was used to allocate it. Agents were added one at a time to a regimen that already worked. Each addition was tested in a population enrolled without regard to receptor status. The record a clinic now uses for this subtype was therefore built largely in patients who were not selected to be in it.
Experiment
Sequential randomised additions and substitutions on an anthracycline backbone. A taxane added after doxorubicin and cyclophosphamide, the interval between cycles shortened with growth factor support, the anthracycline replaced by a taxane and cyclophosphamide, and one taxane and schedule compared against another.
Finding
Adding a taxane improved outcomes, shortening the interval improved them, and one four-cycle anthracycline-free regimen matched a taxane and anthracycline combination while a six-cycle version of the same idea did not. Weekly paclitaxel and three-weekly docetaxel each beat three-weekly paclitaxel.
Limitation
Almost none of this was randomised within this subtype, and the subtype composition of each trial differs. A regimen comparison that enrolled a mixed population reports an average over subtypes whose sensitivity to chemotherapy is not the same, so a result that holds overall may not hold here. The non-inferiority margins were set separately and are not comparable.
Next question
Genomic assays now spare most of this subtype chemotherapy altogether. Is the backbone still the right question, or is the question which patients belong in these trials?

CALGB 9344 NSABP B-28 CALGB 9741 GIM2 US Oncology 9735 ECOG E1199 ABC trials WSG-PlanB

Once chemotherapy is chosen, the remaining questions are which regimen and on what schedule. The pharmacology of each agent belongs to Cytotoxic chemotherapy.

The randomised trials that built the adjuvant backbone.

Three questions are interleaved here, and the experimental-versus-control column is what separates them.

TrialPopulationExperimental vs controlResultOverall survival
WSG-PlanB252449HER2-negative early breast cancer, pT1 to pT4c, node-positive or node-negative with at least one high-risk feature.Four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel versus six cycles of docetaxel and cyclophosphamide.Five-year disease-free survival was 89.6% with epirubicin and cyclophosphamide followed by docetaxel versus 89.9% with six cycles of docetaxel and cyclophosphamide. The difference was within the prespecified noninferiority margin of 4.4%.Five-year overall survival was 94.5% with epirubicin and cyclophosphamide followed by docetaxel versus 94.7% with six cycles of docetaxel and cyclophosphamide.
ABC trials264242Women with high-risk HER2-negative early breast cancer receiving adjuvant chemotherapy.Six cycles of docetaxel and cyclophosphamide vs standard taxane plus anthracycline regimens.Four-year invasive disease-free survival was 88.2% with six cycles of docetaxel and cyclophosphamide and 90.7% with taxane plus anthracycline regimens (P = .04). The hazard ratio for an invasive disease-free survival event was 1.202 (95% CI 0.97 to 1.49), above the predefined inferiority boundary of 1.18, so noninferiority could not be declared.There was no difference in overall survival between the regimens at a median follow-up of 6.9 years.
GIM2272091node-positive early breast cancer, all subtypesevery-2-week dose-dense chemotherapy vs every-3-week, each with or without fluorouracil added to epirubicin, cyclophosphamide and paclitaxel5-year DFS 81% with every-2-week dosing vs 76%; HR 0.77 (0.65-0.92), P=0.004. Fluorouracil added nothing, HR 1.065-year OS 94% vs 89%; HR 0.65 (0.51-0.84), P=0.001
US Oncology 9735281016Women with early breast cancer receiving adjuvant chemotherapy, of whom 16% were aged 65 years or older.Four cycles of docetaxel and cyclophosphamide versus four cycles of doxorubicin and cyclophosphamide.At a median of seven years, disease-free survival was 81% with docetaxel and cyclophosphamide versus 75% with doxorubicin and cyclophosphamide, hazard ratio 0.74, 95% CI 0.56 to 0.98, P = 0.033.Seven-year overall survival was 87% with docetaxel and cyclophosphamide versus 82% with doxorubicin and cyclophosphamide, hazard ratio 0.69, 95% CI 0.50 to 0.97, P = 0.032.
ECOG E1199294950Women with axillary lymph node-positive or high-risk lymph node-negative operable breast cancer, enrolled without regard to receptor subtype.After doxorubicin and cyclophosphamide, paclitaxel or docetaxel, each given every 3 weeks for four cycles or weekly for 12 cycles.Against paclitaxel every 3 weeks, the odds ratio for disease-free survival was 1.27 with weekly paclitaxel (P=0.006), 1.23 with docetaxel every 3 weeks (P=0.02) and 1.09 with weekly docetaxel (P=0.29), an odds ratio above 1 favouring the experimental schedule.Weekly paclitaxel improved overall survival against paclitaxel every 3 weeks, odds ratio 1.32, P=0.01.
NSABP B-28303060Patients with resected operable breast cancer and histologically positive axillary nodes.Four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel versus four cycles of doxorubicin and cyclophosphamide alone.Adding paclitaxel reduced the hazard of a disease-free survival event by 17 percent (relative risk 0.83, 95 percent CI 0.72 to 0.95, P=.006), with five-year disease-free survival of 76 percent versus 72 percent.Five-year overall survival was 85 percent in both groups (relative risk 0.93, 95 percent CI 0.78 to 1.12, P=.46), so the difference was not significant.
CALGB 9344313121Women with operable breast cancer and involved axillary lymph nodes after surgical treatment.Four cycles of doxorubicin and cyclophosphamide at three doxorubicin doses, then four cycles of paclitaxel versus no further therapy.Adding paclitaxel after doxorubicin and cyclophosphamide reduced the hazard of recurrence by 17% (p=0.0023), with 5-year disease-free survival of 70% versus 65%. Escalating doxorubicin gave no benefit, with 5-year disease-free survival of 69%, 66% and 67% at 60, 75 and 90 mg/m2.Five-year overall survival was 80% with paclitaxel versus 77% without, an 18% reduction in the hazard of death (p=0.0064).
CALGB 9741322005node-positive operable breast cancer, all subtypesevery-2-week dose-dense chemotherapy with filgrastim vs every-3-week chemotherapy, in a 2 x 2 with sequential vs concurrent scheduling4-year DFS 82% with dose-dense vs 75%; risk ratio 0.74, P=0.010risk ratio 0.69, P=0.013

The eight trials answer three questions that are habitually read as one, and they agree on one thing across all three. Every increment here is a few percentage points of disease-free survival, and none of the modern comparisons found a regimen that was clearly wrong.

Whether a taxane should follow an anthracycline was asked by CALGB 9344 and NSABP B-28. Both found the same relative reduction in disease-free survival events and diverged on survival, which CALGB 9344 improved and NSABP B-28 did not31,30. Nothing about the taxane differs between them. CALGB 9344 also randomised three doxorubicin doses and found no dose effect, which is the more durable result in that row. Its unplanned subgroup analysis put the recurrence hazard ratio at 0.72 in oestrogen receptor-negative and 0.91 in receptor-positive tumours31. That single comparison does more to explain the position of taxanes in this subtype than either trial's headline.

Inside that same question sits the choice of taxane and schedule, which ECOG E1199 asked directly. The answer is a pairing rather than a class. Weekly paclitaxel beat three-weekly paclitaxel on disease-free and overall survival. Docetaxel every three weeks also beat three-weekly paclitaxel on disease-free survival. Weekly docetaxel did not29. A trial with four arms is the only design that could have shown that. Its price was grade 2 to 4 neuropathy in 27% of the weekly paclitaxel arm against 20% of the control.

Whether the interval between cycles carries an independent effect was asked by CALGB 9741 and GIM2, twelve years apart, on different backbones. Both are positive on disease-free and overall survival. Both also carried a second randomisation that added nothing, to concurrent against sequential scheduling in CALGB 9741 and to fluorouracil in GIM232,27. The schedule effect is the only claim in this table reproduced on two independent backbones, which is why it is more secure than any single agent addition.

Whether the anthracycline can come out altogether was asked by US Oncology 9735, ABC trials and WSG-PlanB. Those three appear to disagree and largely do not, because they did not use the same control arm. US Oncology 9735 compared four cycles of docetaxel and cyclophosphamide with four cycles of doxorubicin and cyclophosphamide, which is an anthracycline regimen containing no taxane28. It is evidence that a taxane doublet beats an old doublet. It is not evidence about the modern comparator.

ABC trials and WSG-PlanB both used that modern comparator, setting six cycles of docetaxel and cyclophosphamide against a regimen containing a taxane and an anthracycline. Both returned small differences, and the two point estimates do not favour the same arm. Their verdicts differ because their margins were set on different scales. ABC set an inferiority boundary on the hazard ratio at 1.18 and returned 1.202, so non-inferiority could not be declared26. PlanB set a margin of 4.4 percentage points of disease-free survival and cleared it25. The trials also differ in follow-up at the time of the verdict and in how their randomised populations were assembled, because PlanB removed its lowest genomic risk stratum from randomisation altogether. ABC has since reported with longer follow-up33. Read the margin before reading the conclusion.

Two structural points are specific to this subtype, and one of them is about the table itself. Six of these eight trials enrolled without regard to receptor status, so they appear here on the all-comers wildcard rather than because they enrolled this population. Their estimates are averages over a population in which hormone receptor-positive disease was the part least likely to benefit. The absolute gain from anthracycline-containing over taxane-based regimens is small in endocrine-responsive disease, and the trial-level comparisons that establish it are in34. Schedule, by contrast, carries an independent effect established across 37,298 women in 26 trials35.

The practical consequence is that dose density is available without adding an agent. In a subtype where the marginal benefit of chemotherapy is contested, changing the schedule is a cheaper lever than changing the drugs.

References

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