Revisión bibliográfica

Sesiones Interhospitalarias Madrileñas de Cáncer de Mama

César Gómez Raposo FEA Oncología Médica

Hospital Infanta Sofía, San Sebastián de los Reyes, Madrid

Agenda • Genómica.

• Tratamiento neoadyuvante.

• CM Her2+.

• CM RH+ Her2-.

• CDIS. Quimioprevención.

• Radioterapia.

• Revisiones. Guías clínicas.

• Toxicidades de los tratamientos.

• Estudios preclínicos.

GENÓMICA

• N = 3198 pts → 15,3% RS ≤ 11 • F-Up 35 m, 3-y DFS:

– 98% – 92% RS >25 vs 98% RS 12-25

• Multivariate factors: – Nodal status – Local and central grade – RS

pN0-1. RS ≥ 12 treated with ChT

TRATAMIENTO NEOADYUVANTE

HER, human epidermal growth factor receptor; HR, hormone receptor; nab-P, nab-paclitaxel; sb-P, solvent-based paclitaxel.

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• Inclusion criteria: – cT2 - cT4a-d

– cT1c and cN+ or ER- and PR- or Ki67 > 20% or HER2 +

• pCR (ypT0N0): – 38,4% vs 29%, OR 1,53 (95%

CI 1,20-1,95, p=0,00054)

Peripheral sensory neuropathy grade 3-4: - 10% patients receiving any nab-paclitaxel dose; - 8% of patients starting with 125 mg/m2 - 15% of patients starting with 150 mg/m2

• Several questions remain: – Survival data still inmature – expected in 2018 – Heterogeneus population

– Half of patients with HR +ve and HER2-ve – Not statistically significant improvement in pCR

– TNBC: pCR 26% vs 38%: effect of clinical relevance – Definite conclusions are still premature – Peripheral sensory neuropathy significantly higher

– Long-term data on quality of life

• 2811 HER2 + → 21,4% HER2 –

• 9947 HER2- → 3,4% HER2 +

• 10973 ER+ve → 4,6% ER-ve

• 5607 ER-ve → 9,3% ER+ve

CÁNCER DE MAMA HER2+

• Stage 1-3 Her2+

• Neo-/adjuvant Trast therapy up to 2y

→ Stage 2-3 who had completed Trast therapy up to 1y

• N=2840 pts

• 12 months of neratinib vs placebo

• Stratified by: HR status, nodal status, Trast regimen (seq vs conc.)

• Toxicity: Diarrhoea

• Grade 3 40%

• Grade 2 72%

• 17% disconuations

70 vs 120

93,9% vs 91,6%

Primary endpoint: invasive DFS at 2y

Posibility that the biological effect of neratinib could be related to a reversal of

endocrine resistance though mechanisms independent of HER2

Whether neratinib is a clinically meaningful treatment strategy and its place in

the treatment landscape for early-stage HER2-positive breast cancer will

depend on the results of both the adjuvant APHINITY trial and effective

toxicity management, and on a better understanding of risk stratification.

Multivariable analysis:

-- treatment arm

-- intrinsic subtype

-- HER2 amplicon gene

expression

--p53 mutation signature,

-- immune cell signatures

Post-treatment residual

disease was largely luminal

A (69%).

10-year RFS: high and low levels of STILs

-- arm A: 90.9%and 64.5%

HR, 0.23 [95%CI, 0.07-0.73]; P = .01).

-- arm C: 80.0% and 80.1%

HR, 1.26 [95%CI, 0.50-3.17]; P = .63).

CÁNCER DE MAMA RH+ HER2-

• disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy

• oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (IM injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant

• N=521 pts

• Stratified by: sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis

• Evaluation endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline

Not related to the degree of endocrine sensitivity assessed clinically or

pathologically (ie, levels of expression of oestrogen and progesterone

recpetors) or to PI3K mutational status.

• Next-generation sequencing

CIN scoring system

• 302 specimens

• NO correlations between Everolimus benefit and genetic alterations in the PI3K/mTOR Pathway, FGFR and Cell-Cycle Control Genes

• PIK3CA exon-9 mutations more benefit than exon-20 mutations

• Randomly assigned (1:1) either to taxane (docetaxel 60–75 mg/m² 3–4 weeks; paclitaxel 80–100 mg/m² weekly for 3 of 4 weeks; or paclitaxel 175 mg/m² 3–4 weeks) or to S-1 (40–60 mg twice daily for 28 consecutive days, followed by a 14-day break)

• Stratification by: liver metastasis, ER and PgR status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence

• N=618 pts. Median F-Up 34,6 m

• Primary endpoint: OS

• 35 m (S1) vs 37,2m (taxanes), HR 1,05, [95% CI 0·86–1·27]; p=0·015

• Subgroup analyses:

• TNBC: HR 1,29 (95% CI 0,88-1,89 in favour taxanes)

• Liver metastasis: HR 1,22 (95% CI 0,88-1,68 in favour taxanes)

CDIS QUIMIOPREVENCIÓN

• N = 3104. HR+ve DCIS.

• Median F-Up 9y

• Primary objective: BC-free interval

• 122 tamoxifen vs 90 anastrozole; HR 0·73 [95% CI 0·56–0·96]; p=0·023

• benefit only in ≤ 60 years (HR 0·53 [95% CI 0·35–0·80], p=0·0026)

• N = 2980. HR+ve DCIS.

• Locally excised ± RT

• Median F-Up 7,2y

• Primary objective: all recurrences

• 77 tamoxifen vs 67 anastrozole; HR 0·89 [95% CI 0·64–1,23]; p=0·49

RADIOTERAPIA

3.890 pts

F-Up 9y

OS: 75,9% vs 72,2%, HR 0,82, 95% CI 0,72-0,94, p=0.005

Subgroup analyses: effect more pronounced in pts

- many nodes involved

- medial/central tumors

1,184 pts

≥ 40 y

- pT1–2a (≤3 cm)

- pN0/pNmi

- microscopically resection margins

of at least 2 mm (ILC or DCIS, at

least 5 mm)

- no LVI

- low/intermediate risk DCIS

GUÍAS CLÍNICAS REVISIONES

Higher risk pts (tumor size, nodal status, age, grade) should receive OS in addition to adj ET

Stage II-III BC who ordinarily be advised to adj ChT should receive OS in addition to adj ET

Stage I BC not warranting ChT should receive ET but not OS

OS may be administered with either Tamoxifen or AI (AI for higher risk and younger)

Sufficient evidence of clinical utility for biomarkers assys OncoType DX, EndoPredict,

PAM50, Breast Cancer Index and urokinase plasminogen activator and plasminogen

activator inhibitor type 1 in specific subgroups of BC.

Biphosphonates (either IV ZA or oral clodronate) are considered as part of the adj BC

treatment in all pts with a T score <-2.0 o ≥ 2 clinical risk factors for fracture and in post-

menopausal woment or those receving OST.

TOXICIDADES DE LOS TRATAMIENTOS

• 88 survivors of BC with TRL

• 21% inherited mutations in BRCA1, BRCA2, TP53, CHEK2 and PALB2

• genes involved in DNA damage response and repair pathways

• Link between BC germline gene mutations and development of TRL

• Genetic testing in specific subsets of pts after a diagnosis of early BC may potentially

identify those for close monitoring of hematologic parameters

ESTUDIOS PRECLÍNICOS

• Inhibidores desplazan a proteínas bromodominio BET (BRD4) de la cromatina -> inhibición de procesos de transcripción

• Líneas celulares con resistencia adquirida a inhibición BET continúan siendo dependientes de BRD4 -> estrategia de combinación para prevenir/revertir resistencia